US6140332A - Pyrrolopyrimidines and processes for the preparation thereof - Google Patents

Pyrrolopyrimidines and processes for the preparation thereof Download PDF

Info

Publication number
US6140332A
US6140332A US08/981,877 US98187798A US6140332A US 6140332 A US6140332 A US 6140332A US 98187798 A US98187798 A US 98187798A US 6140332 A US6140332 A US 6140332A
Authority
US
United States
Prior art keywords
phenyl
carbamoyl
pyrimidine
pyrrolo
lower alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
US08/981,877
Other languages
English (en)
Inventor
Peter Traxler
Guido Bold
Wolfgang Karl-Diether Brill
Jorg Frei
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis AG
Original Assignee
Novartis AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=27508793&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US6140332(A) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Novartis AG filed Critical Novartis AG
Assigned to NOVARTIS AG reassignment NOVARTIS AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: FREI, JORG, BRILL, WOLFGANG KARL-DIETHER, BOLD, GUIDO, TRAXLER, PETER
Application granted granted Critical
Publication of US6140332A publication Critical patent/US6140332A/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention relates to 7H-pyrrolo[2,3-d]pyrimidine derivatives and to processes and novel intermediates for the preparation thereof, to pharmaceutical formulations comprising such derivatives and to the use of those derivatives as medicaments.
  • the invention relates to 7H-pyrrolo[2,3-d]pyrimidine derivatives of formula I ##STR2## wherein q is 0 or 1,
  • n is from 1 to 3 when q is 0, or n is from 0 to 3 when q is 1,
  • R is halogen, lower alkyl, hydroxy, lower alkanoyloxy, lower alkoxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl, N,N-di-lower alkyl-carbamoyl, cyano, amino, lower alkanoylamino, lower alkylamino, N,N-di-lower alkylamino or tri-fluoromethyl, it being possible when several radicals R are present in the molecule for those radicals to be identical or different,
  • R 1 and R 2 are each independently of the other
  • phenylamino that is unsubstituted or substituted in the phenyl moiety by halogen, lower alkyl, hydroxy, lower alkanoyloxy, lower alkoxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl, N,N-di-lower alkyl-carbamoyl, cyano, amino, lower alkanoylamino, lower alkylamino, N,N-di-lower alkylamino or by trifluoromethyl,
  • radicals R 1 and R 2 when q is 0, one of the radicals R 1 and R 2 is unsubstituted lower alkyl or unsubstituted phenyl and the other of the radicals R 1 and R 2 has one of the meanings given above in paragraph a) with the exception of hydrogen, or
  • R 1 and R 2 together are C 4 -C 10 -1,4-alkadienylene substituted by amino, lower alkanoylamino, lower alkylamino, N,N-di-lower alkylamino, nitro, halogen, hydroxy, lower alkanoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl, N,N-di-lower alkyl-carbamoyl or by cyano, or are aza-1,4-alkadienylene having up to 9 carbon atoms, or d) when q is 1, R 1 and R 2 are each independently of the other unsubstituted lower alkyl or unsubstituted phenyl or have one of the meanings given above in paragraph
  • R 6 is hydrogen, lower alkyl, lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl or N,N-di-lower alkyl-carbamoyl,
  • lower used hereinbefore and hereinafter denotes a radical having up to and including a maximum of 7, especially up to and including a maximum of 4, and above all 1 or 2, carbon atoms.
  • n is 2 or especially 1.
  • that substituent is preferably in the 3-position on the phenyl ring.
  • those substituents are preferably in the 3- and 4-positions.
  • Halogen R is bromine, iodine or preferably fluorine or chlorine.
  • n is 1, R is preferably chlorine.
  • Lower alkyl is, for example, methyl.
  • Lower alkanoyloxy is, for example, acetoxy.
  • Lower alkoxy is, for example, methoxy.
  • Lower alkoxycarbonyl is, for example, methoxycarbonyl.
  • N-Lower alkyl-carbamoyl is, for example, N-methyl-carbamoyl, N-(n-butyl)-carbamoyl or N-(3-methyl-but-1-yl)-carbamoyl.
  • N,N-Di-lower alkyl-carbamoyl is, for example, N,N-di-methyl-carbamoyl.
  • Lower alkanoylamino is, for example, acetylamino.
  • Lower alkylamino is, for example, methylamino.
  • N,N-Di-lower alkylamino is, for example, dimethylamino.
  • Lower alkoxycarbonyl-methoxy is, for example, methoxycarbonyl-methoxy.
  • Substituted phenyl R 1 or R 2 may carry one or more, but preferably not more than three, substituents which may be identical or different. Substituted phenyl R 1 or R 2 preferably carries only one substituent which may be in the ortho-, the meta- or, preferably, the para-position.
  • Phenyl-substituted phenyl R 1 or R 2 is, for example, biphenylyl, preferably 4-biphenylyl.
  • Pyridyl is, for example, 2-pyridyl.
  • Halogen in a radical R 1 or R 2 is fluorine, bromine, iodine or preferably chlorine.
  • Naphthyl is, for example, 2-naphthyl.
  • Lower alkenyl is, for example, vinyl, prop-1-enyl or prop-2-enyl (allyl).
  • Lower alkenyloxy is, for example, vinyloxy, prop-1-enyloxy or prop-2-enyloxy (allyloxy).
  • Substituted lower alkyl R 1 or R 2 may carry one or more, but preferably not more than three, substituents, which may be identical or different. Substituted lower alkyl R 1 or R 2 preferably carries only one substituent.
  • C 4 -C 10 -1,4-Alkadienylene is a divalent buta-1,3-diene radical in which each of terminal carbon atoms Nos. 1 and 4 has a free valency and which can be substituted by lower alkyl, the radical as a whole, however, having not more than 10 carbon atoms, for example buta-1,3-dien-1,4-ylene.
  • Aza-1,4-alkadienylene having up to 9 carbon atoms is C 4 -C 10 -1,4-alkadienylene as defined above in which at least one carbon atom, preferably a carbon atom of the butadiene chain, such as especially a terminal carbon atom of the butadiene chain, has been replaced by nitrogen, for example 1-aza-1,4-alkadienylene, such as especially 1-aza-buta-1,3-dien-1,4-ylene.
  • Aza-1,4-alkadienylene preferably contains from 1 to 3 nitrogen atoms, especially only one.
  • 1-Aza-1,4-alkadienylene having only one nitrogen atom is preferably bonded via that nitrogen atom to carbon atom 6 of the 7H-pyrrolo[2,3-d]pyrimidine ring system.
  • Salts of compounds of formula I are especially acid addition salts with organic or inorganic acids, especially the pharmaceutically acceptable, non-toxic salts.
  • Suitable inorganic acids are, for example, carbonic acid (preferably in the form of the carbonates or hydrogen carbonates); hydrohalic acids, such as hydrochloric acid; sulfuric acid; or phosphoric acid.
  • Suitable organic acids are, for example, carboxylic, phosphonic, sulfonic or sulfamic acids, for example acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, 2-hydroxybutyric acid, gluconic acid, glucosemonocarboxylic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid, citric acid, glucaric acid, galactaric acid, amino acids, such as glutamic acid, aspartic acid, N-methylglycine, acetylaminoacetic acid, N-acetylasparagine or N-acetylcystine, pyruvic acid, acetoacetic acid, phosphoserine, 2- or 3-glycerophosphoric acid, glucose-6-phosphoric acid, glucose-1-phosphoric acid, fructo
  • Compounds of formula I having at least one free carboxy group are capable of forming internal salts or metal or ammonium salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, or ammonium salts with ammonia or suitable organic amines, such as tertiary monoamines, for example triethylamine or tri(2-hydroxyethyl)amine, or heterocyclic bases, for example N-ethyl-piperidine or N,N'-dimethyl-piperazine.
  • internal salts or metal or ammonium salts such as alkali metal or alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, or ammonium salts with ammonia or suitable organic amines, such as tertiary monoamines, for example triethylamine or tri(2-hydroxyethyl)amine, or heterocyclic bases, for example N-ethyl-piperidine or N,N'-dimethyl-
  • salts for isolation or purification purposes it is also possible to use pharmaceutically unacceptable salts, for example picrates or perchlorates. Only salts that are pharmaceutically acceptable and non-toxic (at the appropriate dosages) are used therapeutically and those salts are therefore preferred.
  • the compounds of formula I have valuable pharmacologically useful properties. In particular they exhibit specific inhibitory activities that are of pharmacological interest. They are effective especially as tyrosine protein kinase inhibitors and/or (furthermore) as inhibitors of serine/threonine protein kinases; they exhibit, for example, powerful inhibition of the tyrosine kinase activity of the receptor for epidermal growth factor (EGF) and of c-erbB2 kinase. Those receptor-specific enzyme activities play a key role in signal transmission in a large number of mammalian cells, including human cells, especially epithelial cells, cells of the immune system and cells of the central and peripheral nervous system.
  • EGF epidermal growth factor
  • EGF-induced activation of receptor-associated tyrosine protein kinase is a prerequisite for cell division and hence for the proliferation of the cell population.
  • An increase in the number of EGF-receptor-specific tyrosine kinase inhibitors thus inhibits the proliferation of the cells.
  • the compounds of formula I also inhibit to varying extents other tyrosine protein kinases that are involved in signal transmission mediated by trophic factors, for example abl kinase, especially v-abl kinase, kinases from the family of the src kinases, especially c-src kinase, Ick, fyn; other kinases of the EGF family, for example c-erbB2 kinase e (HER-2), c-erbB3 kinase, c-erbB4 kinase; members of the family of the PDGF-receptor tyrosine protein kinases, for example PDGF-receptor kinase, CSF-1 receptor kinase, Kit-receptor kinase, VEGF-receptor kinase (e.
  • abl kinase especially v-abl kinase
  • KDR and Flt-1 Flt-1 and FGF-receptor kinase
  • FGF-receptor kinase the receptor kinase of the insulin-like growth factor (IGF-1 kinase)
  • IGF-1 kinase insulin-like growth factor
  • serine/threonine kinases for example protein kinase C or cdc kinases, all of which play a part in growth regulation and transformation in mammalian cells, including human cells.
  • EGF-receptor-specific tyrosine protein kinase (EGF-R-TPK) can be demonstrated using known methods, for example using the recombinant intracellular domain of the EGF-receptor (EGF-R ICD; see, for example, E. McGlynn et al., Europ. J. Biochem. 207, 265-275 (1992)).
  • the compounds of formula I inhibit the enzyme activity by 50% (IC 50 ), for example in a concentration of from 0.0005 to 1 ⁇ M, especially from 0.001 to 0.1 ⁇ M.
  • the action of the compounds of formula I on EGF-stimulated cellular tyrosine phosphorylation in the EGF-receptor can be determined in the human A431 epithelial carcinoma cell line by means of an ELISA which is described in U. Trinks et al., J. Med. Chem. 37:7, 1015-1027 (1994). In that test (EGFR-ELISA) the compounds of formula I exhibit an IC 50 of approximately from 0.001 to 1 ⁇ M.
  • the compounds of formula I exhibit, for example, inhibition of the cell growth of EGF-dependent cell lines, for example the epidermoid BALB/c mouse keratinocyte cell line (see Weissmann, B. A., and Aaronson, S. A., Cell 32, 599 (1983)) or the A431 cell line, which are recognized useful standard sources of EGF-dependent epithelial cells (see Carpenter, G., and Zendegni, J. Anal. Biochem. 153, 279-282 (1985)).
  • EGF-dependent cell lines for example the epidermoid BALB/c mouse keratinocyte cell line (see Weissmann, B. A., and Aaronson, S. A., Cell 32, 599 (1983)) or the A431 cell line, which are recognized useful standard sources of EGF-dependent epithelial cells (see Carpenter, G., and Zendegni, J. Anal. Biochem. 153, 279-282 (1985)).
  • a known test method see Meyer e
  • the inhibitory activity of the compounds of formula I is determined, briefly, as follows: BALB/MK cells (10 000/microtiter plate well) are transferred to 96-well microtiter plates. The test compounds (dissolved in DMSO) are added in a series of concentrations (dilution series) in such a manner that the final concentration of DMSO is not greater than 1% (v/v). After the addition, the plates are incubated for three days during which the control cultures without test compound are able to undergo at least three cell-division cycles.
  • the growth of the MK cells is measured by means of methylene blue staining: after the incubation the cells are fixed with glutaraldehyde, washed with water and stained with 0.05% methylene blue. After a washing step the stain is eluted with 3% HCl and the optical density per well of the microtitre plate is measured using a Titertek Multiskan at 665 nm. IC 50 values are determined by a computer-aided system using the formula:
  • the IC 50 value in those experiments is given as that concentration of the test compound in question that results in a cell count that is 50% lower than that obtained using the control without inhibitor.
  • the compounds of formula I exhibit inhibitory activity in the micromolar range, for example an IC 50 of approximately from 0.1 to 1 ⁇ M.
  • the compounds of formula I exhibit inhibition of the growth of tumor cells also in vivo, as shown, for example, by the test described below: the test is based on inhibition of the growth of the human epidermoid carcinoma A431 (ATCC No. CRL 1555; American Type Culture Collection, Rockville, Md., USA; see Santon, J. B., et al., Cancer Research 46, 4701-4705 (1986) and Ozawa, S., et al., Int. J. Cancer 40, 706-710 (1987)), which is transplanted into female BALB/c nude mice (Bomholtgard, Denmark). That carcinoma exhibits a growth that correlates with the extent of the expression of the EGF-receptor.
  • tumors having a volume of approximately 1 cm 3 cultured in vivo are surgically removed from experimental animals under sterile conditions.
  • the tumors are comminuted and suspended in 10 volumes (w/v) of phosphate-buffered saline.
  • the suspension is injected s.c. (0.2 ml/mouse in phosphate-buffered saline) into the left flank of the animals.
  • s.c. 0.2 ml/mouse in phosphate-buffered saline
  • 1 ⁇ 10 6 cells from an in vitro culture in 0.2 ml of phosphate-buffered saline can be injected.
  • Treatment with test compounds of formula I is started 5 or 7 days after the transplant, when the tumors have reached a diameter of 4-5 mm.
  • the test compound in question is administered (in different doses for different animal groups) once a day for 15 successive days.
  • the tumor growth is determined by measuring the diameter of the tumors along three axes that are perpendicular to each other.
  • the tumor volumes are calculated using the known formula p ⁇ L ⁇ D 2 /6 (see Evans, B. D., et al., Brit. J. Cancer 45, 466-8 (1982)).
  • T/C % values of less than 10 indicates strong inhibition of tumor growth.
  • the compounds of formula I also inhibit other tyrosine protein kinases that are involved in signal transmission mediated by trophic factors, for example abl kinase, such as especially v-abl kinase (IC 50 for example from 0.01 to 5 ⁇ M), kinases from the family of the src kinases, such as especially c-src kinase (IC 50 for example from 0.1 to 10 ⁇ M) and c-erbB2 kinase (HER-2), and serine/threonine kinases, for example protein kinase C, all of which are involved in growth regulation and transformation in mammalian cells, including human cells.
  • abl kinase such as especially v-abl kinase (IC 50 for example from 0.01 to 5 ⁇ M)
  • src kinases such as especially c-src kinase (IC 50 for example from 0.1 to 10 ⁇ M) and c-erb
  • c-erbB2 tyrosine kinase HER-2
  • the inhibition of c-erbB2 tyrosine kinase can be determined, for example, analogously to the method used for EGF-R-TPK (see C. House et al, Europ. J. Biochem. 140, 363-367 (1984)).
  • the c-erbB2 kinase can be isolated, and its activity determined, by means of protocols known per se, for example in accordance with T. Akiyama et a., Science 232, 1644 (1986).
  • the compounds of formula I which inhibit the tyrosine kinase activity of the receptor for the epidermal growth factor (EGF) or of the other tyrosine protein kinases mentioned are therefore useful, for example, in the treatment of benign or malignant tumors. They are capable of effecting tumor regression and of preventing the formation of tumor metastases and the growth of micrometastases. They can be used especially in the case of epidermal hyperproliferation (psoriasis), in the treatment of neoplasias of epithelial character, e.g. mammary carcinomas, and in leukemias.
  • the compounds of formula I can be used in the treatment of those disorders of the immune system in which several or, especially, individual tyrosine protein kinases and/or (furthermore) serine/threonine protetin kinases are involved; those compounds of formula I can also be used in the treatment of those disorders of the central or peripheral nervous system in which signal transmission by several or, especially, a single tyrosine protein kinase(s) and/or (furthermore) serine/threonine protein kinase(s) is/are involved.
  • the present invention relates also to the use of the compounds of formula I in the inhibition of the mentioned protein kinases.
  • the compounds according to the invention can be used both alone and in combination with other pharmacologically active compounds, for example together with inhibitors of the enzymes of polyamine synthesis, inhibitors of protein kinase C, inhibitors of other tyrosine kinases, cytokines, negative growth regulators, for example TGF- ⁇ or IFN- ⁇ , aromatase inhibitors, antiestrogens and/or cytostatic drugs.
  • n is from 1 to 3 when q is 0, or n is from 0 to 3 when q is 1,
  • R is halogen, lower alkyl, hydroxy, lower alkanoyloxy, lower alkoxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl, N,N-di-lower alkyl-carbamoyl, cyano, amino, lower alkanoylamino, lower alkylamino, N,N-di-lower alkylamino or trifluoromethyl, it being possible when several radicals R are present in the molecule for those radicals to be identical or different,
  • R 1 and R 2 are each independently of the other phenyl substituted by carbamoylmethoxy, carboxy-methoxy, benzyloxycarbonyl-methoxy, lower alkoxycarbonyl-methoxy, phenyl, amino, lower alkanoylamino, lower alkylamino, N,N-di-lower alkyl-amino, hydroxy, lower alkanoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl, N,N-di-lower alkyl-carbamoyl, cyano or by nitro; hydrogen; unsubstituted or halo- or lower alkyl-substituted pyridyl; N-benzyl-pyridinium-2-yl; naphthyl; cyano; carboxy; lower alkoxycarbonyl; carbamoyl; N-lower alkyl-car
  • R 1 and R 2 together are C 4 -C 10 -1,4-alkadienylene substituted by amino, lower alkanoylamino, lower alkylamino, N,N-di-lower alkylamino, nitro, halogen, hydroxy, lower alkanoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl, N,N-di-lower alkyl-carbamoyl or by cyano, or are aza-1,4-alkadienylene having up to 9 carbon atoms, or
  • R 1 and R 2 are each independently of the other unsubstituted lower alkyl or unsubstituted phenyl or have one of the meanings given above in paragraph a), and
  • R 6 is hydrogen, lower alkyl, lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl or N,N-di-lower alkyl-carbamoyl, and to the salts thereof, with the exception of the compound of formula I wherein n is 0, q is 1, R 1 and R 6 are each hydrogen and R 2 is methyl.
  • n is from 1 to 3 when q is 0, or n is from 0 to 3 when q is 1,
  • R is halogen, lower alkyl, hydroxy, lower alkanoyloxy, lower alkoxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl, N,N-di-lower alkyl-carbamoyl, cyano, amino, lower alkanoylamino, lower alkylamino, N,N-di-lower alkylamino or trifluoromethyl, it being possible when several radicals R are present in the molecule for those radicals to be identical or different,
  • R 1 is hydrogen and R 2 is phenyl substituted by carbamoylmethoxy, carboxy-methoxy, benzyloxycarbonyl-methoxy, lower alkoxycarbonyl-methoxy, phenyl, amino, lower alkanoylamino, lower alkylamino, N,N-di-lower alkylamino, hydroxy, lower alkanoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl, N,N-di-lower alkyl-carbamoyl, cyano or by nitro; unsubstituted or halo- or lower alkyl-substituted pyridyl; N-benzyl-pyridinium-2-yl; naphthyl; cyano; carboxy; lower alkoxycarbonyl; carbamoyl; N-lower alkyl-carbamoyl; N
  • radicals R 1 and R 2 when q is 0, one of the radicals R 1 and R 2 is unsubstituted lower alkyl or unsubstituted phenyl and the other of the radicals R 1 and R 2 has one of the meanings given above in paragraph a) with the exception of hydrogen, or
  • R 1 and R 2 together are C 4 -C 10 -1,4-alkadienylene substituted by lower alkanoyl-amino, nitro, halogen, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl, N,N-di-lower alkyl-carbamoyl or by cyano, or are aza-1,4-alkadienylene having up to 9 carbon atoms, or
  • R 1 is hydrogen and R 2 is unsubstituted phenyl
  • R 6 is hydrogen, lower alkyl, lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl or N,N-di-lower alkyl-carbamoyl, and to the salts thereof.
  • R 1 and R 2 are each independently of the other phenyl substituted by phenyl, amino, lower alkanoylamino, lower alkylamino, N,N-di-lower alkylamino, hydroxy, lower alkanoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl, N,N-di-lower alkyl-carbamoyl, cyano or by nitro; hydrogen; unsubstituted or halo- or lower alkyl-substituted pyridyl; N-benzyl-pyridinium-2-yl; naphthyl; cyano; carboxy; lower alkoxycarbonyl; carbamoyl; N-lower alkyl-carbamoyl; N,N-di-lower alkyl-carbamoyl; formyl; lower alkanoyl; lower alkenyl;
  • one of the radicals R 1 and R 2 is unsubstituted lower alkyl or unsubstituted phenyl and the other of the radicals R 1 and R 2 has one of the meanings given above in paragraph a) with the exception of hydrogen, or
  • R 1 and R 2 together are C 4 -C 10 -1,4-alkadienylene substituted by amino, lower alkanoylamino, lower alkylamino, N,N-di-lower alkylamino, nitro, halogen, hydroxy, lower alkanoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl, N,N-di-lower alkyl-carbamoyl or by cyano, or are aza-1,4-alkadienylene having up to 9 carbon atoms, and to the salts thereof.
  • n is from 1 to 3 and q is 0,
  • R is halogen, lower alkyl, hydroxy, lower alkanoyloxy, lower alkoxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl, N,N-di-lower alkyl-carbamoyl, cyano, amino, lower alkanoylamino, lower alkylamino, N,N-di-lower alkylamino or trifluoromethyl, it being possible when several radicals R are present in the molecule for those radicals to be identical or different, and
  • R 1 and R 2 are each independently of the other phenyl substituted by phenyl, amino, lower alkanoylamino, lower alkylamino, N,N-di-lower alkylamino, hydroxy, lower alkanoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl, N,N-di-lower alkyl-carbamoyl, cyano or by nitro; unsubstituted or halo- or lower alkyl-substituted pyridyl; N-benzyl-pyridinium-2-yl; naphthyl; cyano; carboxy; lower alkoxy-carbonyl; carbamoyl; N-lower alkyl-carbamoyl; N,N-di-lower alkyl-carbamoyl; ormyl; lower alkanoyl; lower alkenyl; lower alken
  • one of the radicals R 1 and R 2 is hydrogen, unsubstituted lower alkyl or unsubstituted phenyl and the other of the radicals R 1 and R 2 has one of the meanings given above in paragraph a), or
  • R 1 and R 2 together are C 4 -C 10 -1,4-alkadienylene substituted by amino, lower alkanoylamino, lower alkylamino, N,N-di-lower alkylamino, nitro, halogen, hydroxy, lower alkanoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl, N,N-di-lower alkyl-carbamoyl or by cyano, or are aza-1,4-alkadienylene having up to 9 carbon atoms, and to the salts thereof.
  • n 1 or 2 and q is 0,
  • R is halogen, it being possible when several radicals R are present in the molecule for those radicals to be identical or different, and
  • R 1 and R 2 are each independently of the other phenyl substituted by phenyl, amino, hydroxy or by nitro; hydrogen; pyridyl; N-benzyl-pyridinium-2-yl; naphthyl; or lower alkyl substituted by di-lower alkylamino, or
  • one of the radicals R 1 and R 2 is unsubstituted lower alkyl or unsubstituted phenyl and the other of the radicals R 1 and R 2 has one of the meanings given above in paragraph a) with the exception of hydrogen, or
  • R 1 and R 2 together are aza-1,4-alkadienylene having up to 9 carbon atoms, and to the salts thereof.
  • n 1 or 2 and q is 0,
  • R is halogen, it being possible when several radicals R are present in the molecule for those radicals to be identical or different, and
  • R 1 is hydrogen, or lower alkyl unsubstituted or substituted by di-lower alkylamino
  • R 2 is phenyl substituted by phenyl, amino, hydroxy or by nitro; pyridyl; N-benzylpyridinium-2-yl; or naphthyl, or
  • R 1 and R 2 together are aza-1,4-alkadienylene having up to 9 carbon atoms, and to the salts thereof.
  • n is from 0 to 3
  • R is halogen, lower alkyl, hydroxy, lower alkanoyloxy, lower alkoxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl, N,N-di-lower alkyl-carbamoyl, cyano, amino, lower alkanoylamino, lower alkylamino, N,N-di-lower alkylamino or trifluoromethyl, it being possible when several radicals R are present in the molecule for those radicals to be identical or different,
  • R 1 and R 2 are each independently of the other phenyl substituted by carbamoylmethoxy, carboxy-methoxy, benzyloxycarbonyl-methoxy, lower alkoxycarbonyl-methoxy, phenyl, amino, lower alkanoylamino, lower alkylamino, N,N-di-lower alkylamino, hydroxy, lower alkanoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl, N,N-di-lower alkyl-carbamoyl, cyano or by nitro; hydrogen; unsubstituted or halo- or lower alkyl-substituted pyridyl; N-benzyl-pyridinium-2-yl; naphthyl; cyano; carboxy; lower alkoxycarbonyl; carbamoyl; N-lower alkyl-carbam
  • R 1 and R 2 together are C 4 -C 10 -1,4-alkadienylene substituted by amino, lower alkanoylamino, lower alkylamino, N,N-di-lower alkylamino, nitro, halogen, hydroxy, lower alkanoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl, N,N-di-lower alkyl-carbamoyl or by cyano, or are aza-1,4-alkadienylene having up to 9 carbon atoms, or
  • R 1 and R 2 are each independently of the other unsubstituted lower alkyl or unsubstituted phenyl or have one of the meanings given above in paragraph a), and R 6 is hydrogen, lower alkyl, lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl or N,N-di-lower alkyl-carbamoyl, and to the salts thereof.
  • n is 1 or 2 when q is 0, or n is from 0 to 2 when q is 1,
  • R is halogen or lower alkyl, it being possible when several radicals R are present in the molecule for those radicals to be identical or different, and
  • R 1 is hydrogen, or lower alkyl that is unsubstituted or substituted by di-lower alkylamino
  • R 2 is phenyl substituted by carbamoylmethoxy, carboxymethoxy, benzyloxycarbonylmethoxy, lower alkoxycarbonylmethoxy, lower alkoxycarbonyl, carboxy, N,N-di-lower alkyl-carbamoyl, phenyl, amino, lower alkylamino, di-lower alkylamino, lower alkanoylamino, hydroxy or by nitro; hydroxy-lower alkyl, amino-lower alkyl, di-lower alkylamino-lower alkyl, piperazino-lower alkyl, formyl, cyano, carboxy; lower alkoxycarbonyl; carbamoyl, N-lower alkyl-carbamoyl; N,N-di-lower alkyl-carbamoy
  • R 1 and R 2 together are 1-aza-buta-1,3-dien-1,4-ylene, or
  • R 1 and R 2 are each methyl
  • R 6 is hydrogen, methyl or lower alkoxycarbonyl, and to the salts thereof.
  • n is 1 or 2 when q is 0, or n is from 0 to 2 when q is 1,
  • R is halogen, it being possible when several radicals R are present in the molecule for those radicals to be identical or different, and
  • R 1 is hydrogen or lower alkyl that is unsubstituted or substituted by di-lower alkylamino
  • R 2 is phenyl substituted by carbamoylmethoxy, carboxymethoxy, benzyloxycarbonylmethoxy, methoxycarbonylmethoxy, ethoxycarbonyl, carboxy, phenyl, amino, acetamino, hydroxy or by nitro; carboxy; ethoxycarbonyl; N-lower alkyl-carbamoyl; pyridyl; N-benzyl-pyridinium-2-yl; or naphthyl, or
  • R 1 and R 2 together are aza-1,4-alkadienylene having up to 9 carbon atoms, or
  • R 1 and R 2 are each methyl, and R 6 is hydrogen, methyl or methoxycarbonyl, and to the salts thereof.
  • the invention relates also to the compound 4-(3-chloro-anilino)-pyrimido[4,5-b]indole, which does not fall within the scope of formula I, which is obtainable in accordance with Example (Reference Example) 15, and to the pharmaceutically acceptable salts thereof.
  • the compounds of formula I and the salts thereof are prepared by processes known per se.
  • the process according to the invention comprises
  • the end products of formula I may contain substituents that can also be used as protecting groups in starting materials for the preparation of other end products of formula 1.
  • protecting group is used in this text to denote only a readily removable group that is not a constituent of the particular desired end product of formula I.
  • a suitable leaving group X is preferably halogen, such as bromine, iodine or especially chlorine.
  • 1-Aryl-lower alkyl Z is preferably 1-phenyl-lower alkyl, such as especially 1-phenylethyl or, more especially, benzyl.
  • Free functional groups present in the radicals R 1 and R 2 which are if necessary protected by readily removable protecting groups, are especially amino or lower alkylamino.
  • a protected amino group may be present, for example, in the form of a readily cleavable acylamino, arylmethylamino, etherified mercaptoamino or 2-acyl-lower alk-1-enyl-amino group.
  • acyl is, for example, the acyl radical of an organic carboxylic acid having, for example, up to 18 carbon atoms, especially an unsubstituted or substituted, for example halo- or aryl-substituted, alkanecarboxylic acid or an unsubstituted or substituted, for example halo-, lower alkoxy- or nitro-substituted, benzoic acid, or of a carbonic acid semiester.
  • an organic carboxylic acid having, for example, up to 18 carbon atoms, especially an unsubstituted or substituted, for example halo- or aryl-substituted, alkanecarboxylic acid or an unsubstituted or substituted, for example halo-, lower alkoxy- or nitro-substituted, benzoic acid, or of a carbonic acid semiester.
  • Such acyl groups are, for example, lower alkanoyl, such as formyl, acetyl or propionyl, halo-lower alkanoyl, such as 2-haloacetyl, especially 2-chloro-, 2-bromo-, 2-iodo-, 2,2,2-tri-fluoro- or 2,2,2-trichloro-acetyl, unsubstituted or substituted, for example halo-, lower alkoxy- or nitro-substituted, benzoyl, for example benzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl or 4-nitrobenzoyl, or lower alkoxycarbonyl that is branched in the 1-position of the lower alkyl radical or suitably substituted in the 1- or 2-position, especially tert-lower alkoxycarbonyl, for example tert-butoxycarbonyl, arylmethoxycarbonyl having one or two aryl radicals which are preferably phen
  • aryl radicals are especially unsubstituted or substituted phenyl radicals.
  • aryl radicals are, for example, benzyl-, diphenylmethyl- and especially trityl-amino.
  • An etherified mercapto group in an amino group protected by such a radical is especially arylthio or aryl-lower alkylthio, wherein aryl is, especially, phenyl that is unsubstituted or substituted, for example, by lower alkyl, such as methyl or tert-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, and/or by nitro.
  • a corresponding amino-protecting group is, for example, 4-nitrophenylthio.
  • acyl is, for example, the corresponding radical of a lower alkanecarboxylic acid, of a benzoic acid that is unsubstituted or substituted, for example, by lower alkyl, such as methyl or tert-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, and/or by nitro, or especially of a carbonic acid semiester, such as a carbonic acid lower alkyl semiester.
  • lower alkyl such as methyl or tert-butyl
  • lower alkoxy such as methoxy
  • halogen such as chlorine
  • nitro or especially of a carbonic acid semiester, such as a carbonic acid lower alkyl semiester.
  • Corresponding protecting groups are especially 1-lower alkanoyl-prop-1-en-2-yl, such as 1-acetyl-prop-1-en-2-yl, or 1-lower alkoxycarbonyl-prop-1-en-2-yl, for example 1-ethoxycarbonyl-prop-1-en-2-yl.
  • Preferred amino-protecting groups are acyl radicals of carbonic acid semiesters, especially tert-butyloxycarbonyl, benzyloxycarbonyl that is unsubstituted or substituted, for example as indicated, for example 4-nitro-benzyloxycarbonyl, or diphenylmethoxycarbonyl, or 2-halo-lower alkoxycarbonyl, such as 2,2,2-trichloroethoxycarbonyl, also trityl or formyl.
  • the reaction between the derivative of formula II and the amine of formula III takes place in suitable inert polar solvents, especially alcohols, for example lower alkanols, such as methanol, propanol, isopropanol or especially ethanol or n-butanol.
  • suitable inert polar solvents especially alcohols, for example lower alkanols, such as methanol, propanol, isopropanol or especially ethanol or n-butanol.
  • a solubilizer such as 1 ,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU)
  • DMPU 1 ,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone
  • the reaction takes place at elevated temperatures, for example in a temperature range of from 70 to 150° C., preferably under reflux conditions.
  • Z in the compound of formula II is 1-aryl-lower alkyl
  • protonic acids such as hydrochloric acid, phosphoric acids or polyphosphoric acid
  • the removal of the protecting groups that are not constituents of the desired end product of formula I is effected in a manner known per se, for example by means of solvolysis, especially hydrolysis, alcoholysis or acidolysis, or by means of reduction, especially hydrogenolysis or chemical reduction, where appropriate step-wise or simultaneously.
  • a protected amino group is freed in a manner known per se and, according to the nature of the protecting groups, in various ways, preferably by solvolysis or reduction.
  • 2-Halo-lower alkoxycarbonylamino (where appropriate after conversion of a 2-bromo-lower alkoxycarbonylamino group into a 2-iodo-lower alkoxycarbonylamino group), aroylmethoxycarbonylamino or 4-nitrobenzyloxycarbonylamino can be cleaved, for example, by treatment with a suitable chemical reducing agent, such as zinc in the presence of a suitable carboxylic acid, such as aqueous acetic acid.
  • a suitable chemical reducing agent such as zinc in the presence of a suitable carboxylic acid, such as aqueous acetic acid.
  • Aroylmethoxycarbonylamino can be cleaved also by treatment with a nucleophilic, preferably salt-forming, reagent, such as sodium thiophenolate, and 4-nitrobenzyloxycarbonylamino also by treatment with an alkali metal dithionite, for example sodium dithionite.
  • a nucleophilic, preferably salt-forming, reagent such as sodium thiophenolate
  • 4-nitrobenzyloxycarbonylamino also by treatment with an alkali metal dithionite, for example sodium dithionite.
  • Unsubstituted or substituted diphenylmethoxycarbonylamino, tert-lower alkoxycarbonylamino or 2-trisubstituted silylethoxycarbonylamino can be cleaved by treatment with a suitable acid, for example formic acid or trifluoroacetic acid; unsubstituted or substituted benzyloxycarbonylamino can be cleaved, for example, by means of hydrogenolysis, i.e.
  • unsubstituted or substituted triarylmethylamino or formylamino can be cleaved, for example, by treatment with an acid, such as a mineral acid, for example hydrochloric acid, or an organic acid, for example formic, acetic or trifluoroacetic acid, where appropriate in the presence of water; and an amino group protected by an organic silyl group can be freed, for example, by means of hydrolysis or alcoholysis.
  • a suitable hydrogenation catalyst such as a palladium catalyst
  • an acid such as a mineral acid, for example hydrochloric acid, or an organic acid, for example formic, acetic or trifluoroacetic acid, where appropriate in the presence of water
  • an amino group protected by an organic silyl group can be freed, for example, by means of hydrolysis or alcoholysis.
  • An amino group protected by 2-haloacetyl for example 2-chloroacetyl
  • 2-chloroacetyl can be freed by treatment with thiourea in the presence of a base, or with a thiolate salt, such as an alkali metal thiolate, of thiourea, and subsequent solvolysis, such as alcoholysis or hydrolysis, of the resulting condensation product.
  • An amino group protected by 2-substituted silylethoxycarbonyl can be converted into the free amino group also by treatment with a salt of hydrofluoric acid that yields fluoride anions.
  • 1-Aryl-lower alkyl Z' in a compound of formula IV is especially 1-phenylethyl and also benzyl.
  • the compound of formula IV is in tautomeric equilibrium (lactam/lactim form), the lactam form (formula IV) presumably predominating.
  • Formula IV is used to represent the two possible equilibrium forms.
  • the lactim form has the formula IVa ##STR7## wherein the radicals are as defined for compounds of formula IV.
  • the present invention relates likewise to the novel compounds of formulae IV and IVa.
  • dehydrating agent especially a strong chemical dehydrating agent, especially phosphorus pentoxide (P 4 O 10 ).
  • Suitable as tertiary amine is especially ammonia substituted by three radicals selected independently of one another from alkyl, especially lower alkyl, such as methyl or ethyl, and cycloalkyl having from 3 to 7 carbon atoms, especially cyclohexyl, for example N,N-dimethyl-N-cyclohexylamine, N-ethyl-N,N-diisopropylamine or triethylamine, or, furthermore, also pyridine, N-methylmorpholine or 4-dimethylaminopyridine.
  • reaction between the pyrrolo-pyrimidinone of formula IV and the amine of formula III takes place at elevated temperature, for example at from 200 to 250° C.
  • reaction is carried out with the exclusion of moisture in a suitable inert solvent, for example a suitable ether, such as a cyclic ether, such as especially tetrahydrofuran, at elevated temperature, preferably under reflux.
  • a suitable inert solvent for example a suitable ether, such as a cyclic ether, such as especially tetrahydrofuran, at elevated temperature, preferably under reflux.
  • the reaction is carried out with the exclusion of moisture in a suitable inert solvent, for example a suitable halogenated hydrocarbon, such as especially methylene chloride, at temperatures of from approximately -20° C. to +50° C., preferably with ice-cooling or at room temperature.
  • a suitable inert solvent for example a suitable halogenated hydrocarbon, such as especially methylene chloride
  • the hydrogenation is carried out under elevated pressure or preferably under normal pressure in the presence of a suitable hydrogenation catalyst, such as especially Raney nickel, in an inert solvent or solvent mixture, such as especially a mixture of a suitable cyclic ether and a suitable lower alkanol, such as preferably a mixture of tetrahydrofuran and methanol, at temperatures of approximately from 0° C. to +50° C., preferably at room temperature.
  • a suitable hydrogenation catalyst such as especially Raney nickel
  • an inert solvent or solvent mixture such as especially a mixture of a suitable cyclic ether and a suitable lower alkanol, such as preferably a mixture of tetrahydrofuran and methanol
  • the starting materials of formula II are novel and the present invention relates also thereto. They can be prepared by processes analogous to those described in German Offenlegungsschrift No. 28 18 676 (published Nov. 8, 1979) and German Offenlegungsschrift No. 30 36 390 (published on May 13, 1982).
  • the starting material of formula II wherein X is chlorine is obtained, for example, from a compound analogous to formula II wherein X is hydroxy by reaction with phosphorus oxychloride (phosphoryl chloride, P( ⁇ O)Cl 3 ) with the exclusion of moisture at the reflux temperature.
  • phosphorus oxychloride phosphoryl chloride, P( ⁇ O)Cl 3
  • the further reaction of the starting material of formula II thus obtained wherein X is chlorine can be carried out with an amine of formula III in the same vessel, i.e. as a one-pot reaction.
  • reaction mixture from that reaction is concentrated to dryness by evaporation, made into a suspension with a suitable solvent, such as n-butanol, and reacted further with the amine of formula Ill.
  • a compound analogous to formula II wherein X is hydroxy is obtained, for example, from a compound of formula V ##STR8## wherein the substituents are as defined above, by reaction with formic acid which is preferably used in excess relative to the compound of formula V, for example in a 10 to 30 molar excess, where appropriate in the presence of inert solvents, such as dimethylformamide, at elevated temperature, for example at temperatures of from 80° C. to the boiling temperature.
  • formic acid which is preferably used in excess relative to the compound of formula V, for example in a 10 to 30 molar excess, where appropriate in the presence of inert solvents, such as dimethylformamide, at elevated temperature, for example at temperatures of from 80° C. to the boiling temperature.
  • a compound analogous to formula II wherein X is hydroxy and the remaining symbols are as defined above is obtained, for example, from a compound of formula VI ##STR9## wherein R 4 is lower alkyl, such as especially ethyl, and the remaining symbols are as defined above, by reaction with a large excess of formamide in a mixture of anhydrous dimethylformamide and formic acid.
  • the reaction is carried out at elevated temperature, for example at from 100° C. to 150° C., and preferably under a protecting gas.
  • the present invention relates also to the novel starting materials of formulae V and VI.
  • the 1-(Z')-2-amino-3-cyano-pyrroles of formula V used as intermediates can be prepared in good yields by methods that are known per se and have been published [see, for example, Roth, H. J., and Eger, K., Arch. Pharmaz. 308, 179 (1975)].
  • a compound of formula VII ##STR10## is reacted first with an amine of the formula Z'-NH 2 to form a compound of formula VIII ##STR11## which is then converted with malonic acid dinitrile of the formula CH 2 (CN) 2 into the desired intermediate of formula V.
  • reaction with the amine Z'-NH 2 is carried out under customary condensation conditions, for example in the presence of catalytic amounts of a strong acid, for example hydrochloric acid or p-toluenesulfonic acid, at elevated temperature (preferably at the boiling temperature) in a suitable solvent, for example benzene or toluene, with the removal of water, to form the respective ⁇ -amino ketone of formula VII.
  • a strong acid for example hydrochloric acid or p-toluenesulfonic acid
  • a suitable solvent for example benzene or toluene
  • the compounds of formula VI wherein R 2 is N-benzyl-pyridinium-2-yl and the remaining symbols are as defined above that are used as intermediates are obtained, for example, by reacting a compound of formula VI wherein R 2 is hydrogen and the remaining symbols are as defined above with N-benzyl-2-bromo-pyridinium bromide in a suitable solvent, such as a halogenated hydrocarbon, such as especially methylene chloride.
  • a suitable solvent such as a halogenated hydrocarbon, such as especially methylene chloride.
  • the reaction is preferably carried out under a protective gas, in the dark and under anhydrous conditions at room temperature or elevated temperature, for example at from 20° C. to 80° C., and in the presence of 2,6-dimethyl-pyridine (2,6-lutidine).
  • the remaining compounds of formula VI are obtained, for example, by reacting a 2-amidino-acetic acid lower alkyl ester of formula IX ##STR12## wherein R 4 is as defined above, with a 2-X-1-R 2 -ethan-1-one derivative of formula X ##STR13## wherein the substituents are as defined above.
  • the leaving group X is preferably bromine.
  • the 2-amidino-acetic acid lower alkyl ester of formula IX is freed from its acid addition salt, such as especially its hydrochloride, before the start of the reaction with the aid of equinormal amounts of a base, such as especially sodium ethanolate, with ice-cooling.
  • the reaction is carried out in a suitable solvent, such as especially a lower alkanol, such as preferably ethanol, at preferred temperatures of from 0° C. to 50° C., especially at room temperature.
  • Free compounds of formula I having salt-forming properties that are obtainable according to the process can be converted into their salts in a manner known per se, for example by treatment with acids or suitable derivatives thereof, for example by the addition of the appropriate acid to the compound of formula I dissolved in a suitable solvent, for example an ether, such as a cyclic ether, especially dioxane or more especially tetrahydrofuran.
  • a suitable solvent for example an ether, such as a cyclic ether, especially dioxane or more especially tetrahydrofuran.
  • Mixtures of isomers obtainable according to the invention can be separated into the individual isomers in a manner known per se; racemates can be separated, for example, by forming salts with optically pure salt-forming reagents and separating the mixture of diastereoisomers thus obtainable, for example by means of fractional crystallization.
  • the reactions described above can be carried out under reaction conditions known per se, in the absence or, customarily, the presence of solvents or diluents, preferably those that are inert towards the reagents used and are solvents therefor, in the absence or presence of catalysts, condensation agents (for example phosphorus pentoxide) or neutralizing agents, for example bases, especially nitrogen bases, such as triethylamine hydrochloride, depending on the nature of the reaction and/or of the reactants at reduced, normal or elevated temperature, for example in a temperature range of from approximately -80° C. to approximately 200° C., preferably from approximately -20° C. to approximately 150° C., for example at the boiling point of the solvent used, under atmospheric pressure or in a closed vessel, where appropriate under pressure, and/or in an inert atmosphere, for example under a nitrogen atmosphere.
  • condensation agents for example phosphorus pentoxide
  • neutralizing agents for example bases, especially nitrogen bases, such as triethylamine hydrochloride
  • Solvents and diluents are, for example, water, alcohols, for example lower alkyl hydroxides, such as methanol, ethanol, propanol or especially butanol, diols, such as ethylene glycol, triols, such as glycerol, or aryl alcohols, such as phenol, acid amides, for example carboxylic acid amides, such as dimethylformamide, dimethylacetamide or 1 ,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), carboxylic acids, especially formic acid or acetic acid, amides of inorganic acids, such as hexamethyl-phosphoric acid triamide, ethers, for example cyclic ethers, such as tetrahydrofuran or dioxane, or acyclic ethers, such as diethyl ether or ethylene glycol dimethyl ether, halogenated hydrocarbons, such as hal
  • Customary processes are used for working up the obtainable compounds of formula I or the salts thereof, for example solvolysis of excess reagents; recrystallization; chromatography, for example partition, ion or gel chromatography; partitioning between inorganic and organic solvent phases; single or multiple extraction, especially after acidifying or increasing the basicity or the salt content; drying over hygroscopic salts; digesting; filtering; washing; dissolving; concentrating by evaporation (if necessary in vacuo or under a high vacuum); distillation; crystallization, for example of compounds obtained in oil form or from the mother liquor, inoculation with a crystal of the end product also being possible; or a combination of two or more of the mentioned working-up steps, which can also be used repeatedly, etc.
  • Starting materials and intermediates can be used in pure form, for example after working-up, as just mentioned, in partly purified form or also, for example, directly in the form of the crude product.
  • any reference to the free compounds and their salts is to be understood as including also the corresponding salts and free compounds, respectively, as appropriate and expedient, provided that the compounds contain salt-forming groups.
  • the compounds, including their salts, may also be obtained in the form of hydrates, or their crystals may include, for example, the solvent used for crystallization.
  • the starting materials used are preferably those that lead to the novel compounds of formula I described at the beginning as being especially valuable.
  • the invention relates also to those forms of the process according to which a compound obtainable as intermediate at any stage of the process is used as starting material and the remaining process steps are carried out or in which a starting material is formed under the reaction conditions or is used in the form of a derivative, for example a salt, thereof.
  • the invention relates especially to a process for the preparation of a 7H-pyrrolo[2,3-d]-pyrimidine derivative of formula Ia, which falls within the scope of formula I ##STR14## and wherein n is from 1 to 3,
  • R is hydrogen, halogen, lower alkyl, hydroxy, lower alkanoyloxy, lower alkoxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl, N,N-di-lower alkyl-carbamoyl, cyano, amino, lower alkanoylamino, lower alkylamino, N,N-di-lower alkylamino or trifluoromethyl, it being possible when several radicals R are present in the molecule for those radicals to be identical or different, and
  • R 1 and R 2 are each independently of the other phenyl substituted by phenyl, amino, lower alkanoylamino, lower alkylamino, N,N-di-lower alkylamino, hydroxy, lower alkanoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl, N,N-di-lower alkyl-carbamoyl, cyano or by nitro; hydrogen; unsubstituted or halo- or lower alkyl-substituted pyridyl; N-benzyl-pyridinium-2-yl; naphthyl; cyano; carboxy; lower alkoxycarbonyl; carbamoyl; N-lower alkyl-carbamoyl; N,N-di-lower alkyl-carbamoyl; formyl; lower alkanoyl; lower alkenyl;
  • one of the radicals R 1 and R 2 is unsubstituted lower alkyl or unsubstituted phenyl and the other of the radicals R 1 and R 2 has one of the meanings given above in paragraph a) with the exception of hydrogen, or
  • R 1 and R 2 together are C 4 -C 10 -1,4-alkadienylene that is unsubstituted or substituted by amino, lower alkanoylamino, lower alkylamino, N,N-di-lower alkylamino, nitro, halogen, hydroxy, lower alkoxy, lower alkanoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl, N,N-di-lower alkyl-carbamoyl or by cyano, or are aza-1,4-alkadienylene having up to 9 carbon atoms, or a salt thereof,
  • the invention relates also to a pyrrolo[2,3-d]pyrimidine derivative of formula IIa ##STR18## wherein X' is hydroxy or a suitable leaving group, Z is hydrogen or 1-aryl-lower alkyl,
  • R 1 is hydrogen or lower alkyl that is unsubstituted or substituted by di-lower alkylamino
  • R 2 is
  • phenylamino that is unsubstituted or substituted in the phenyl moiety by halogen, lower alkyl, hydroxy, lower alkanoyloxy, lower alkoxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl, N,N-di-lower alkyl-carbamoyl, cyano, amino, lower alkanoylamino, lower alkylamino, N,N-di-lower alkylamino or by trifluoromethyl,
  • the invention relates also to pyrrolo[2,3-d]pyrimidine derivatives of formula IIa ##STR19## wherein X' is hydroxy or a leaving group, Z is hydrogen or 1-aryl-lower alkyl, and
  • R 1 and R 2 are each independently of the other phenyl substituted by carbamoylmethoxy, carboxy-methoxy, benzyloxycarbonyl-methoxy, lower alkoxycarbonyl-methoxy, phenyl, amino, lower alkanoylamino, lower alkylamino, N,N-di-lower alkylamino, hydroxy, lower alkanoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl, N,N-di-lower alkyl-carbamoyl, cyano or by nitro; hydrogen; unsubstituted or halo- or lower alkyl-substituted pyridyl; N-benzyl-pyridinium-2-yl; naphthyl; cyano; carboxy; lower alkoxycarbonyl; carbamoyl; N-lower alkyl-carbam
  • one of the radicals R 1 and R 2 is unsubstituted lower alkyl or unsubstituted phenyl and the other of the radicals R 1 and R 2 has one of the meanings given above in paragraph a) with the exception of hydrogen, or
  • R 1 and R 2 together are C 4 -C 10 -1,4-alkadienylene that is unsubstituted or substituted by amino, lower alkanoylamino, lower alkylamino, N,N-di-lower alkylamino, nitro, halogen, hydroxy, lower alkoxy, lower alkanoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl, N,N-di-lower alkyl-carbamoyl or by cyano, or are aza-1,4-alkadienylene having up to 9 carbon atoms, and to the 4-keto derivatives that are tautomers of the compounds of formula IIa wherein X' is hydroxy,
  • the invention relates especially to pyrrolo[2,3-d]pyrimidine derivatives of formula IIa wherein X' is hydroxy or a leaving group,
  • Z is hydrogen or 1-aryl-lower alkyl
  • R 1 and R 2 are each independently of the other phenyl substituted by phenyl, amino, lower alkanoylamino, lower alkylamino, N,N-di-lower alkylamino, hydroxy, lower alkanoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl, N,N-di-lower alkyl-carbamoyl, cyano or by nitro; hydrogen; unsubstituted or halo- or lower alkyl-substituted pyridyl; N-benzyl-pyridinium-2-yl; naphthyl; cyano; carboxy; lower alkoxycarbonyl; carbamoyl; N-lower alkyl-carbamoyl; N,N-di-lower alkyl-carbamoyl; formyl; lower alkanoyl; lower alkenyl;
  • one of the radicals R 1 and R 2 is unsubstituted lower alkyl or unsubstituted phenyl and the other of the radicals R 1 and R 2 has one of the meanings given above in paragraph a) with the exception of hydrogen, or
  • R 1 and R 2 together are C 4 -C 10 -1, 4 -alkadienylene that is unsubstituted or substituted by amino, lower alkanoylamino, lower alkylamino, N,N-di-lower alkylamino, nitro, halogen, hydroxy, lower alkoxy, lower alkanoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl, N,N-di-lower alkyl-carbamoyl or by cyano, or are aza-1, 4 -alkadienylene having up to 9 carbon atoms, and to the 4-keto derivatives that are tautomers of the compounds of formula IIa wherein X' is hydroxy,
  • the invention relates also to pyrrole derivatives of formula XI ##STR20## wherein Z is hydrogen or 1-aryl-lower alkyl, a) R 1 is hydrogen or lower alkyl that is unsubstituted or substituted by di-lower alkylamino, and
  • phenylamino that is unsubstituted or substituted in the phenyl moiety by halogen, lower alkyl, hydroxy, lower alkanoyloxy, lower alkoxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl, N,N-di-lower alkyl-carbamoyl, cyano, amino, lower alkanoylamino, lower alkylamino, N,N-di-lower alkylamino or by trifluoromethyl,
  • R 1 and R 2 together are aza-1,4-alkadienylene having up to 9 carbon atoms, and R 5 is cyano or lower alkoxycarbonyl,
  • the invention relates especially to pyrrole derivatives of formula XI wherein Z is hydrogen or 1-aryl-lower alkyl,
  • R 1 and R 2 are each independently of the other phenyl substituted by phenyl, amino, lower alkanoylamino, lower alkylamino, N,N-di-lower alkylamino, hydroxy, lower alkanoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl, N,N-di-lower alkyl-carbamoyl, cyano or by nitro; hydrogen; unsubstituted or halo- or lower alkyl-substituted pyridyl; N-benzyl-pyridinium-2-yl; naphthyl; cyano; carboxy; lower alkoxycarbonyl; carbamoyl; N-lower alkyl-carbamoyl; N,N-di-lower alkyl-carbamoyl; formyl; lower alkanoyl; lower alkenyl;
  • one of the radicals R 1 and R 2 is unsubstituted lower alkyl or unsubstituted phenyl and the other of the radicals R 1 and R 2 has one of the meanings given above in paragraph a) with the exception of hydrogen, or
  • R 1 and R 2 together are C 4 -C 10 -1,4-alkadienylene that is unsubstituted or substituted by amino, lower alkanoylamino, lower alkylamino, N,N-di-lower alkylamino, nitro, halogen, hydroxy, lower alkoxy, lower alkanoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl, N,N-di-lower alkyl-carbamoyl or by cyano, or are aza-1,4-alkadienylene having up to 9 carbon atoms,
  • R 5 is cyano or lower alkoxycarbonyl
  • the pyrrole derivatives of formula XI can be used as starting materials of formulae V and VI shown above and are prepared analogously to those starting materials.
  • the invention relates also to intermediates of formulae IIa and XI wherein the substituents are so defined that the compounds of formula I according to claim 1 are obtained.
  • compositions comprising those compounds as active ingredient
  • compositions that comprise one of the compounds of formula I as active ingredient and that can be used especially in the treatment of the diseases mentioned above.
  • Compositions for enteral administration such as nasal, buccal, rectal or, especially, oral administration, and for parenteral administration, such as intravenous, intramuscular or subcutaneous administration, to warm-blooded animals, especially humans, are especially preferred.
  • the compositions comprise the active ingredient on its own or, preferably, together with a pharmaceutically acceptable carrier.
  • the dosage of the active ingredient depends upon the disease to be treated and upon the species, its age, weight and individual condition, the individual pharmacokinetic data, the disease to be treated and also upon the mode of administration.
  • the invention relates also to pharmaceutical compositions for use in a method for the therapeutic treatment of the human or animal body, to a process for the preparation thereof (especially in the form of compositions for the treatment of tumors) and to a method of treating tumor diseases, especially those mentioned above.
  • a pharmaceutical composition that is suitable for administration to a warm-blooded animal, especially a human, suffering from a disease that is responsive to the inhibition of a protein kinase, for example psoriasis or a tumor, comprising a compound of formula I, or a salt thereof when salt-forming groups are present, in an amount effective in the inhibition of protein kinase, together with at least one pharmaceutically acceptable carrier.
  • the pharmaceutical compositions comprise from approximately 1% to approximately 95% active ingredient, dosage forms in single dose form preferably comprising from approximately 20% to approximately 90% active ingredient and dosage forms that are not in single dose form preferably comprising from approximately 5% to approximately 20% active ingredient.
  • Unit dose forms are, for example, dragees, tablets, ampoules, vials, suppositories or capsules.
  • Other forms of administration are, for example, ointments, creams, pastes, foams, tinctures, lipsticks, drops, sprays, dispersions, etc.
  • Examples are capsules, comprising from approximately 0.05 g to approximately 1.0 g of active ingredient.
  • compositions of the present invention are prepared in a manner known per se, for example by means of conventional mixing, granulating, confectioning, dissolving or lyophilizing processes.
  • compositions of the active ingredient Preference is given to the use of solutions of the active ingredient, and also suspensions or dispersions, especially isotonic aqueous solutions, dispersions or suspensions which, for example in the case of lyophilized compositions which comprise the active ingredient on its own or together with a carrier, for example mannitol, can be made up before use.
  • the pharmaceutical compositions may be sterilized and/or may comprise excipients, for example preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, salts for regulating the osmotic pressure and/or buffers and are prepared in a manner known per se, for example by means of conventional dissolving and lyophilizing processes.
  • the solutions or suspensions mentioned may comprise viscosity-increasing substances, such as sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone or gelatin.
  • Suspensions in oil comprise as the oil component the vegetable, synthetic or semi-synthetic oils customary for injection purposes.
  • liquid fatty acid esters that contain as the acid component a long-chained fatty acid having from 8 to 22, especially from 12 to 22, carbon atoms, for example lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, arachidic acid, behenic acid or corresponding unsaturated acids, for example oleic acid, elaidic acid, erucic acid, brassidic acid or linoleic acid, if desired with the addition of antioxidants, for example vitamin E, ⁇ -carotene or 3,5-di-tert-butyl-4-hydroxytoluene.
  • the alcohol component of those fatty acid esters has a maximum of 6 carbon atoms and is a mono- or poly-hydric, for example a mono-, di- or tri-hydric, alcohol, for example methanol, ethanol, propanol, butanol or pentanol or the isomers thereof, but especially glycol and glycerol.
  • fatty acid esters are therefore to be mentioned: ethyl oleate, isopropyl myristate, isopropyl palmitate, "Labrafil M 2375” (polyoxyethylene glycerol trioleate, Gattefosse, Paris), “Labrafil M 1944 CS” (unsaturated polyglycolized glycerides prepared by alcoholysis of apricot kernel oil and consisting of glycerides and polyethylene glycol ester; Gattefosse, France), “Labrasol” (saturated polyglycolized glycerides prepared by alcoholysis of TCM and consisting of glycerides and polyethylene glycol ester, Gattefosse, France) and/or "Miglyol 812" (triglyceride of saturated fatty acids with a chain length of C 8 to C 12 , Huls AG, Germany), but especially vegetable oils, such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil
  • the injection compositions are prepared in customary manner under sterile conditions; the same applies also to introducing the compositions into ampoules or vials and sealing the containers.
  • compositions for oral administration can be obtained, for example, by combining the active ingredient with one or more solid carriers, if desired granulating a resulting mixture, and processing the mixture or granules, if desired or necessary, by the addition of additional excipients, to form tablets or dragee cores.
  • Suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and also binders, such as starches, for example corn, wheat, rice or potato starch, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and/or, if desired, disintegrators, such as the above-mentioned starches, also carboxymethyl starch, crosslinked polyvinylpyrrolidone, alginic acid or a salt thereof, such as sodium alginate.
  • Additional excipients are especially flow conditioners and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol, or derivatives thereof.
  • Dragee cores can be provided with suitable, optionally enteric, coatings, there being used, inter alia, concentrated sugar solutions which may comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Dyes or pigments may be added to the tablets or dragee coatings, for example for identification purposes or to indicate different doses of active ingredient.
  • suitable, optionally enteric, coatings there being used, inter alia, concentrated sugar solutions which may comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose
  • Orally administrable pharmaceutical compositions also include dry-filled capsules consisting of gelatin, and also soft, sealed capsules consisting of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the dry-filled capsules may contain the active ingredient in the form of granules, for example in admixture with fillers, such as corn starch, binders and/or glidants, such as talc or magnesium stearate, and optionally stabilizers.
  • the active ingredient is preferably dissolved or suspended in suitable liquid excipients, such as fatty oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene or propylene glycol, to which stabilizers and detergents, for example of the polyoxyethylene sorbitan fatty acid ester type, may also be added.
  • suitable liquid excipients such as fatty oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene or propylene glycol, to which stabilizers and detergents, for example of the polyoxyethylene sorbitan fatty acid ester type, may also be added.
  • oral dosage forms are, for example, syrups prepared in customary manner which comprise the active ingredient, for example, in suspended form and in a concentration of about 5% to 20%, preferably about 10%, or in a similar concentration that provides a suitable single dose, for example, when administered in measures of 5 or 10 ml.
  • suitable are, for example, powdered or liquid concentrates for the preparation of shakes, for example in milk. Such concentrates may also be packaged in single dose quantities.
  • Suitable rectally administrable pharmaceutical compositions are, for example, suppositories that consist of a combination of the active ingredient and a suppository base.
  • Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.
  • aqueous solutions of an active ingredient in water-soluble form for example in the form of a water-soluble salt, or aqueous injection suspensions that contain viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and, if desired, stabilizers.
  • the active ingredient optionally together with excipients, can also be in the form of a lyophilizate and can be made into a solution prior to parenteral administration by the addition of suitable solvents.
  • Solutions such as are used, for example, for parenteral administration can also be employed as infusion solutions.
  • Preferred preservatives are, for example, antioxidants, such as ascorbic acid, or microbicides, such as sorbic acid or benzoic acid.
  • Ointments are oil-in-water emulsions that contain up to 70%, but preferably from 20% to 50%, water or aqueous phase.
  • Suitable as fatty phase are especially hydrocarbons, for example petroleum jelly, paraffin oil or hard paraffins, which, in order to improve the water-binding capacity, preferably contain suitable hydroxy compounds, such as fatty alcohols or esters thereof, for example cetyl alcohol or wool wax alcohols, such as wool wax.
  • Emulsifiers are corresponding lipophilic substances, such as sorbitan fatty acid esters (Spans), for example sorbitan oleate and/or sorbitan isostearate.
  • Additives to the aqueous phase are, for example, humectants, such as polyalcohols, for example glycerol, propylene glycol, sorbitol and/or polyethylene glycol, and also preservatives and perfumes.
  • humectants such as polyalcohols, for example glycerol, propylene glycol, sorbitol and/or polyethylene glycol, and also preservatives and perfumes.
  • Fatty ointments are anhydrous and contain as base especially hydrocarbons, for example paraffin, petroleum jelly or paraffin oil, also natural or partially synthetic fats, for example coconut fatty acid triglyceride, or preferably hardened oils, for example hydrogenated groundnut oil or castor oil, also fatty acid partial esters of glycerol, for example glycerol mono- and/or di-stearate, and also, for example, the fatty alcohols increasing the water-absorption, emulsifiers and/or additives mentioned in connection with the ointments.
  • hydrocarbons for example paraffin, petroleum jelly or paraffin oil, also natural or partially synthetic fats, for example coconut fatty acid triglyceride, or preferably hardened oils, for example hydrogenated groundnut oil or castor oil, also fatty acid partial esters of glycerol, for example glycerol mono- and/or di-stearate, and also, for example, the fatty alcohols increasing the water-absorption,
  • Creams are oil-in-water emulsions that contain more than 50% water.
  • oily base there are used especially fatty alcohols, for example lauryl, cetyl or stearyl alcohol, fatty acids, for example palmitic or stearic acid, liquid to solid waxes, for example isopropyl myristate, wool wax or beeswax, and/or hydrocarbons, for example petroleum jelly (petrolatum) or paraffin oil.
  • Suitable emulsifiers are surface-active substances having predominantly hydrophilic properties, such as corresponding non-ionic emulsifiers, for example fatty acid esters of polyalcohols or ethylene oxide adducts thereof, such as polyglycerol fatty acid esters or polyoxyethylene sorbitan fatty acid esters (Tweens), and also polyoxyethylene fatty alcohol ethers or fatty acid esters, or corresponding ionic emulsifiers, such as alkali metal salts of fatty alcohol sulfates, for example sodium lauryl sulfate, sodium cetyl sulfate or sodium stearyl sulfate, which are usually used in the presence of fatty alcohols, for example cetyl alcohol or stearyl alcohol.
  • corresponding non-ionic emulsifiers for example fatty acid esters of polyalcohols or ethylene oxide adducts thereof, such as polyglycerol fatty acid esters or polyoxyethylene sorb
  • Additives to the aqueous phase are, inter alia, agents that reduce the drying out of the creams, for example polyalcohols, such as glycerol, sorbitol, propylene glycol and/or polyethylene glycols, and also preservatives and perfumes.
  • polyalcohols such as glycerol, sorbitol, propylene glycol and/or polyethylene glycols, and also preservatives and perfumes.
  • Pastes are creams and ointments having secretion-absorbing powder constituents, such as metal oxides, for example titanium oxide or zinc oxide, also talcum and/or aluminum silicates, the purpose of which is to bind any moisture or secretions present.
  • metal oxides for example titanium oxide or zinc oxide
  • talcum and/or aluminum silicates the purpose of which is to bind any moisture or secretions present.
  • Foams are administered from pressurized containers and are liquid oil-in-water emulsions in aerosol form; halogenated hydrocarbons, such as chlorofluoro-lower alkanes, for example dichlorodifluoromethane and dichlorotetrafluoroethane, or preferably non-halogenated gaseous hydrocarbons, air, N 2 O or carbon dioxide, are used as propellant gases.
  • halogenated hydrocarbons such as chlorofluoro-lower alkanes, for example dichlorodifluoromethane and dichlorotetrafluoroethane, or preferably non-halogenated gaseous hydrocarbons, air, N 2 O or carbon dioxide, are used as propellant gases.
  • oil phase there are used, inter alia, those used above in the case of ointments and creams; the additives mentioned in that connection are also used.
  • Tinctures and solutions generally have an aqueous-ethanolic base to which there are added, inter alia, polyalcohols, for example glycerol, glycols and/or polyethylene glycol, as humectants for reducing evaporation, and fat-restoring substances, such as fatty acid esters with low molecular weight polyethylene glycols, that is to say lipophilic substances that are soluble in the aqueous mixture, as a replacement for the fatty substances removed from the skin by the ethanol, and, if necessary, other adjuncts and additives.
  • polyalcohols for example glycerol, glycols and/or polyethylene glycol
  • humectants for reducing evaporation for glycerol, glycols and/or polyethylene glycol
  • fat-restoring substances such as fatty acid esters with low molecular weight polyethylene glycols, that is to say lipophilic substances that are soluble in the aqueous mixture, as a replacement for the fatty substances removed
  • the invention relates also to a process or a method of treating the above-mentioned pathological conditions, especially those conditions responsive to the inhibition of protein kinases.
  • the compounds of formula I can be administered as such or in the form of pharmaceutical compositions, prophylactically or therapeutically, preferably in an amount effective against the said diseases, to a warm-blooded animal, for example a human, requiring such treatment, the compounds especially being used in the form of pharmaceutical compositions.
  • the daily dose administered is from approximately 0.1 g to approximately 5 g, preferably from approximately 0.5 g to approximately 2 g, of a compound of the present invention.
  • the starting material is prepared as follows:
  • Step 1.1 2-(5-Amino-4-ethoxycarbonyl-1H-pyrrol-2-yl)-N-benzyl-pyridinium bromide
  • Step 1.3 4-Chloro-6-(pyrid-2-yl)-7H-pyrrolo[2,3-d]pyrimidine With the exclusion of moisture, 7.05 g (33.2 mmol) of 6-(pyrid-2-yl)-7H-pyrrolo[2,3-d]-pyrimidin-4-ol and 70 ml of phosphorus oxychloride are heated at boiling for 2 hours. The dark-brown suspension is concentrated by evaporation to a residual volume of 20 ml. The residue is introduced in portions into water, neutralized with solid NaHCO 3 and 0.2 liter of ethyl acetate is added thereto.
  • the starting material is prepared as follows:
  • the starting material is prepared as follows:
  • the starting material is prepared as follows:
  • the starting material is prepared as follows:
  • the starting material is prepared as follows:
  • Step 11.3 4-Chloro-6-(3-methoxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine With the exclusion of moisture, 5.28 g (21.9 mmol) of 6-(3-methoxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ol and 53 ml of phosphorus oxychloride are heated at boiling for 1.5 hours. The reaction mixture is cooled and filtered. The residue is dissolved in ethyl acetate and washed with NaHCO 3 solution, water and brine.
  • Step 11.4 4-(3-Chloro-anilino)-6-(3-methoxy-phenyl)-7H-pyrrolor[2,3-d]pyrimidine 5.68 g (21.9 mmol) of 4-chloro-6-(3-methoxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine and 4.59 ml (43.7 mmol) of 3-chloro-aniline in 75 ml of n-butanol are heated at boiling for 1.5 hours.
  • the starting material is prepared as follows:
  • Step 12.4 4-(3-Chloro-anilino)-6-(4-methoxy-phenyl)-7H-pyrrolor[2,3-d]pyrimidine
  • the aqueous phases are back-extracted once with ethyl acetate and rendered basic with solid sodium carbonate, resulting in a suspension to which ethyl acetate is added, whereupon the solid becomes concentrated in the organic phase.
  • the organic phase is washed neutral with water three times and the aqueous phases are back-extracted with ethyl acetate.
  • the combined organic phases (suspensions) are concentrated by evaporation.
  • the starting material is prepared as follows:
  • the starting material is prepared as follows:
  • Step 15.2 4-(3-Chloro-anilino)-5,6-tetramethylene-7-benzyi-pyrrolor[2,3-d]pyrimidine
  • the starting material is prepared as follows:
  • Step 16.2 4-(3-Chloro-anilino)-5-methyl-6-(4-methoxy-phenyl)-7H-pyrrolo[2,3-d]-pyrimidine
  • the starting material is prepared as follows:
  • the starting material is prepared as follows:
  • Step 8.2 2.6 g (8.6 mmol) of 2-amino-3-ethoxycarbonyl-5-(4-ethoxy-carbonyl-phenyl)-1H-pyrrole are heated at 150° C. under a protective gas overnight with 19 ml of formamide, 8 ml of DMF and 0.6 ml of formic acid.
  • the starting material is obtained as follows:
  • Step 31.1 2-Amino-3-ethoxycarbonyl-5-(3-ethoxycarbonyl-phenyl)-1H-pyrrole
  • the starting material is prepared as follows:
  • Step 39.1 (R)-6-(4-Methoxy-phenyl)-4-[(1-phenyl-ethyl)-amino]-7H-Dyrrolo[2,3-d]-pyrimidine
  • the starting material is prepared as follows:
  • the title compound is obtained as follows: A mixture of 2.165 g (7.5 mmol) of 6-carboxy-4-(3-chloro-anilino)-7H-pyrrolo[2,3-d]pyrimidine (cf. example 42) in 60 ml of THF and 10 ml of DMPU is refluxed for 30 min and then cooled to 0° C. ( ⁇ fine suspension). Then 824 ⁇ l (7.5 mmol) of N-methylmorpholine followed by 981 ⁇ l (7.5 mmol) of isobutyl chloroformate in 10 ml of THF are added dropwise.
  • Preparation process The mentioned substances are pulverized and forced through a sieve of 0.6 mm mesh size. 0.33 g portions of the mixture are introduced into gelatin capsules using a capsule-filling machine.
  • Preparation process The active ingredient is pulverized and suspended in Lauroglycol® (propylene glycol laurate, Gattefosse S.A., Saint Priest, France) and ground in a wet pulverizer to a particle size of approx. from 1 to 3 ⁇ m. 0.419 g portions of the mixture are then introduced into soft gelatin capsules using a capsule-filling machine.
  • Lauroglycol® propylene glycol laurate, Gattefosse S.A., Saint Priest, France
  • Preparation process The active ingredient is pulverized and suspended in PEG 400 (polyethylene glycol having an M, of from approx. 380 to approx. 420, Fluka, Switzerland) and Tween®80 (polyoxyethylene sorbitan monolaurate, Atlas Chem. Ind. Inc., USA, supplied by Fluka, Switzerland) and ground in a wet pulverizer to a particle size of approx. from 1 to 3 ⁇ m. 0.43 g portions of the mixture are then introduced into soft gelatin capsules using a capsule-filling machine.
  • PEG 400 polyethylene glycol having an M, of from approx. 380 to approx. 420, Fluka, Switzerland
  • Tween®80 polyoxyethylene sorbitan monolaurate, Atlas Chem. Ind. Inc., USA, supplied by Fluka, Switzerland
  • 0.43 g portions of the mixture are then introduced into soft gelatin capsules using a capsule-filling machine.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pyrrole Compounds (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Saccharide Compounds (AREA)
US08/981,877 1995-07-06 1996-06-24 Pyrrolopyrimidines and processes for the preparation thereof Expired - Fee Related US6140332A (en)

Applications Claiming Priority (11)

Application Number Priority Date Filing Date Title
CH197695 1995-07-06
CH1976/95 1995-07-06
CH249895 1995-09-01
CH2498/95 1995-09-01
CH3198/95 1995-11-10
CH319895 1995-11-10
CH25596 1996-02-01
CH255/96 1996-02-01
CH1224/96 1996-05-13
CH122496 1996-05-13
PCT/EP1996/002728 WO1997002266A1 (en) 1995-07-06 1996-06-24 Pyrrolopyrimidines and processes for the preparation thereof

Publications (1)

Publication Number Publication Date
US6140332A true US6140332A (en) 2000-10-31

Family

ID=27508793

Family Applications (1)

Application Number Title Priority Date Filing Date
US08/981,877 Expired - Fee Related US6140332A (en) 1995-07-06 1996-06-24 Pyrrolopyrimidines and processes for the preparation thereof

Country Status (25)

Country Link
US (1) US6140332A (pl)
EP (1) EP0836605B1 (pl)
JP (1) JP4146514B2 (pl)
KR (1) KR100437582B1 (pl)
CN (1) CN1100778C (pl)
AT (1) ATE212993T1 (pl)
BR (1) BR9609617B1 (pl)
CA (1) CA2224435C (pl)
CY (1) CY2365B1 (pl)
CZ (1) CZ1598A3 (pl)
DE (1) DE69619114T2 (pl)
DK (1) DK0836605T3 (pl)
EA (1) EA001428B1 (pl)
ES (1) ES2172670T3 (pl)
HU (1) HUP9900330A3 (pl)
IL (1) IL122855A (pl)
MX (1) MX9800215A (pl)
NO (1) NO310359B1 (pl)
NZ (1) NZ312665A (pl)
PL (1) PL188959B1 (pl)
PT (1) PT836605E (pl)
SI (1) SI9620103A (pl)
SK (1) SK398A3 (pl)
TR (1) TR199800012T1 (pl)
WO (1) WO1997002266A1 (pl)

Cited By (167)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6395733B1 (en) * 1995-06-07 2002-05-28 Pfizer Inc Heterocyclic ring-fused pyrimidine derivatives
WO2003030908A3 (en) * 2001-10-09 2003-11-06 Univ Cincinnati Inhibitors of the egf receptor for the treatment of thyroid cancer
WO2003057149A3 (en) * 2001-12-28 2003-12-18 Bayer Ag 4-substituted fused heteropyrimidines and fused hetero-4-pyrimidones
US20040048887A1 (en) * 2002-07-09 2004-03-11 Boehringer Ingelheim Pharma Gmbh & Co. Kg Pharmaceutical compositions based on anticholinergics and EGFR kinase inhibitors
US20040242600A1 (en) * 2001-08-07 2004-12-02 Guido Bold 4-amino-6-phenyl-pyrrolo[2,3-d]pyrimidine derivatives
US20050153989A1 (en) * 2004-01-13 2005-07-14 Ambit Biosciences Corporation Pyrrolopyrimidine derivatives and analogs and their use in the treatment and prevention of diseases
US20060211678A1 (en) * 2004-08-02 2006-09-21 Saleh Ahmed Aryl-amino substituted pyrrolopyrimidine multi-kinase inhibiting compounds
US20080161320A1 (en) * 2006-09-11 2008-07-03 Xiong Cai Fused bicyclic pyrimidines as ptk inhibitors containing a zinc binding moiety
US20080221132A1 (en) * 2006-09-11 2008-09-11 Xiong Cai Multi-Functional Small Molecules as Anti-Proliferative Agents
US20090029973A1 (en) * 2004-06-02 2009-01-29 Takeda Pharmaceutical Company Limited Fused heterocyclic compound
US20090155247A1 (en) * 2005-02-18 2009-06-18 Ashkenazi Avi J Methods of Using Death Receptor Agonists and EGFR Inhibitors
WO2009098715A2 (en) 2008-01-11 2009-08-13 Natco Pharma Limited Novel pyrazolo [3, 4 -d] pyrimidine derivatives as anti -cancer agents
WO2010108127A1 (en) 2009-03-20 2010-09-23 Genentech, Inc. Bispecific anti-her antibodies
US20110053991A1 (en) * 2007-11-19 2011-03-03 Gore Lia Treatment of Histone Deacetylase Mediated Disorders
WO2011060246A2 (en) 2009-11-12 2011-05-19 Genentech, Inc. A method of promoting dendritic spine density
WO2011086053A1 (en) 2010-01-12 2011-07-21 F. Hoffmann-La Roche Ag Tricyclic heterocyclic compounds, compositions and methods of use thereof
WO2011103242A1 (en) 2010-02-18 2011-08-25 Genentech, Inc. Neuregulin antagonists and use thereof in treating cancer
WO2011113802A2 (en) 2010-03-17 2011-09-22 F. Hoffmann-La Roche Ag Imidazopyridine compounds, compositions and methods of use
WO2011130654A1 (en) 2010-04-16 2011-10-20 Genentech, Inc. Fox03a as predictive biomarker for pi3k/akt kinase pathway inhibitor efficacy
EP2386655A2 (en) 2006-09-12 2011-11-16 Genentech, Inc. Methods and compositions for the diagnosis and treatment of lung cancer using KIT or KDG gene as genetic marker
WO2012031027A1 (en) 2010-08-31 2012-03-08 Genentech, Inc. Biomarkers and methods of treatment
WO2012035039A1 (en) 2010-09-15 2012-03-22 F. Hoffmann-La Roche Ag Azabenzothiazole compounds, compositions and methods of use
WO2012066061A1 (en) 2010-11-19 2012-05-24 F. Hoffmann-La Roche Ag Pyrazolopyridines and pyrazolopyridines and their use as tyk2 inhibitors
WO2012085176A1 (en) 2010-12-23 2012-06-28 F. Hoffmann-La Roche Ag Tricyclic pyrazinone compounds, compositions and methods of use thereof as janus kinase inhibitors
WO2013007768A1 (en) 2011-07-13 2013-01-17 F. Hoffmann-La Roche Ag Tricyclic heterocyclic compounds, compositions and methods of use thereof as jak inhibitors
WO2013007765A1 (en) 2011-07-13 2013-01-17 F. Hoffmann-La Roche Ag Fused tricyclic compounds for use as inhibitors of janus kinases
CN102936251A (zh) * 2012-11-05 2013-02-20 上海毕得医药科技有限公司 一种吡咯并[2,3-d]嘧啶衍生物的制备方法
WO2013024011A1 (en) 2011-08-12 2013-02-21 F. Hoffmann-La Roche Ag Indazole compounds, compositions and methods of use
WO2013025853A1 (en) 2011-08-17 2013-02-21 Genentech, Inc. Neuregulin antibodies and uses thereof
WO2013041539A1 (en) 2011-09-20 2013-03-28 F. Hoffmann-La Roche Ag Imidazopyridine compounds, compositions and methods of use
WO2013081645A2 (en) 2011-11-30 2013-06-06 Genentech, Inc. Erbb3 mutations in cancer
WO2013148315A1 (en) 2012-03-27 2013-10-03 Genentech, Inc. Diagnosis and treatments relating to her3 inhibitors
WO2014128235A1 (en) 2013-02-22 2014-08-28 F. Hoffmann-La Roche Ag Methods of treating cancer and preventing drug resistance
WO2014138364A2 (en) 2013-03-06 2014-09-12 Genentech, Inc. Methods of treating and preventing cancer drug resistance
WO2014139326A1 (en) 2013-03-13 2014-09-18 Genentech, Inc. Pyrazolo compounds and uses thereof
WO2014144850A1 (en) 2013-03-15 2014-09-18 Genentech, Inc. Methods of treating cancer and preventing cancer drug resistance
WO2014152358A2 (en) 2013-03-14 2014-09-25 Genentech, Inc. Combinations of a mek inhibitor compound with an her3/egfr inhibitor compound and methods of use
WO2014153030A2 (en) 2013-03-14 2014-09-25 Genentech, Inc. Methods of treating cancer and preventing cancer drug resistance
WO2015035062A1 (en) 2013-09-05 2015-03-12 Genentech, Inc. Antiproliferative compounds
WO2015049325A1 (en) 2013-10-03 2015-04-09 F. Hoffmann-La Roche Ag Therapeutic inhibitors of cdk8 and uses thereof
WO2015058132A2 (en) 2013-10-18 2015-04-23 Genentech, Inc. Anti-rspo antibodies and methods of use
WO2015095423A2 (en) 2013-12-17 2015-06-25 Genentech, Inc. Combination therapy comprising ox40 binding agonists and pd-1 axis binding antagonists
WO2015095418A1 (en) 2013-12-17 2015-06-25 Genentech, Inc. Methods of treating her2-positive cancers using pd-1 axis binding antagonists and anti-her2 antibodies
WO2015153513A1 (en) 2014-03-31 2015-10-08 Genentech, Inc. Anti-ox40 antibodies and methods of use
WO2015153514A1 (en) 2014-03-31 2015-10-08 Genentech, Inc. Combination therapy comprising anti-angiogenesis agents and ox40 binding agonists
WO2016036873A1 (en) 2014-09-05 2016-03-10 Genentech, Inc. Therapeutic compounds and uses thereof
WO2016044694A1 (en) 2014-09-19 2016-03-24 Genentech, Inc. Use of cbp/ep300 and bet inhibitors for treatment of cancer
WO2016057924A1 (en) 2014-10-10 2016-04-14 Genentech, Inc. Pyrrolidine amide compounds as histone demethylase inhibitors
WO2016073282A1 (en) 2014-11-06 2016-05-12 Genentech, Inc. Combination therapy comprising ox40 binding agonists and tigit inhibitors
WO2016073378A1 (en) 2014-11-03 2016-05-12 Genentech, Inc. Assays for detecting t cell immune subsets and methods of use thereof
WO2016077378A1 (en) 2014-11-10 2016-05-19 Genentech, Inc. Substituted pyrrolopyrdines as inhibitors of bromodomain
WO2016077375A1 (en) 2014-11-10 2016-05-19 Genentech, Inc. Bromodomain inhibitors and uses thereof
WO2016077380A1 (en) 2014-11-10 2016-05-19 Genentech, Inc. Substituted pyrrolopyridines as inhibitors of bromodomain
WO2016081384A1 (en) 2014-11-17 2016-05-26 Genentech, Inc. Combination therapy comprising ox40 binding agonists and pd-1 axis binding antagonists
WO2016086200A1 (en) 2014-11-27 2016-06-02 Genentech, Inc. 4,5,6,7-tetrahydro-1 h-pyrazolo[4,3-c]pyridin-3-amine compounds as cbp and/or ep300 inhibitors
WO2016106340A2 (en) 2014-12-23 2016-06-30 Genentech, Inc. Compositions and methods for treating and diagnosing chemotherapy-resistant cancers
WO2016109546A2 (en) 2014-12-30 2016-07-07 Genentech, Inc. Methods and compositions for prognosis and treatment of cancers
WO2016112284A1 (en) 2015-01-09 2016-07-14 Genentech, Inc. (piperidin-3-yl)(naphthalen-2-yl)methanone derivatives and related compounds as inhibitors of the histone demethylase kdm2b for the treatment of cancer
WO2016112298A1 (en) 2015-01-09 2016-07-14 Genentech, Inc. Pyridazinone derivatives and their use in the treatment of cancer
WO2016112251A1 (en) 2015-01-09 2016-07-14 Genentech, Inc. 4,5-dihydroimidazole derivatives and their use as histone demethylase (kdm2b) inhibitors
WO2016123387A1 (en) 2015-01-30 2016-08-04 Genentech, Inc. Therapeutic compounds and uses thereof
WO2016123391A1 (en) 2015-01-29 2016-08-04 Genentech, Inc. Therapeutic compounds and uses thereof
WO2016138114A1 (en) 2015-02-25 2016-09-01 Genentech, Inc. Therapeutic pyridazine compounds and uses thereof
WO2016164480A1 (en) 2015-04-07 2016-10-13 Genentech, Inc. Antigen binding complex having agonistic activity and methods of use
WO2016196298A1 (en) 2015-05-29 2016-12-08 Genentech, Inc. Therapeutic and diagnolstic methods for cancer
WO2016200835A1 (en) 2015-06-08 2016-12-15 Genentech, Inc. Methods of treating cancer using anti-ox40 antibodies and pd-1 axis binding antagonists
WO2016200836A1 (en) 2015-06-08 2016-12-15 Genentech, Inc. Methods of treating cancer using anti-ox40 antibodies
WO2016205320A1 (en) 2015-06-17 2016-12-22 Genentech, Inc. Methods of treating locally advanced or metastatic breast cancers using pd-1 axis binding antagonists and taxanes
WO2017033019A1 (en) 2015-08-26 2017-03-02 Fundación Centro Nacional De Investigaciones Oncológicas Carlos Iii (Cnio) Condensed tricyclic compounds as protein kinase inhibitors
WO2017151502A1 (en) 2016-02-29 2017-09-08 Genentech, Inc. Therapeutic and diagnostic methods for cancer
WO2017180864A1 (en) 2016-04-14 2017-10-19 Genentech, Inc. Anti-rspo3 antibodies and methods of use
WO2017181111A2 (en) 2016-04-15 2017-10-19 Genentech, Inc. Methods for monitoring and treating cancer
WO2017181079A2 (en) 2016-04-15 2017-10-19 Genentech, Inc. Methods for monitoring and treating cancer
WO2017180581A1 (en) 2016-04-15 2017-10-19 Genentech, Inc. Diagnostic and therapeutic methods for cancer
WO2017205538A1 (en) 2016-05-24 2017-11-30 Genentech, Inc. Pyrazolopyridine derivatives for the treatment of cancer
WO2017205536A2 (en) 2016-05-24 2017-11-30 Genentech, Inc. Therapeutic compounds and uses thereof
WO2017214373A1 (en) 2016-06-08 2017-12-14 Genentech, Inc. Diagnostic and therapeutic methods for cancer
CN107592859A (zh) * 2015-05-11 2018-01-16 巴斯夫欧洲公司 制备4‑氨基哒嗪类的方法
WO2018027204A1 (en) 2016-08-05 2018-02-08 Genentech, Inc. Multivalent and multiepitopic anitibodies having agonistic activity and methods of use
WO2018029124A1 (en) 2016-08-08 2018-02-15 F. Hoffmann-La Roche Ag Therapeutic and diagnostic methods for cancer
WO2018068028A1 (en) 2016-10-06 2018-04-12 Genentech, Inc. Therapeutic and diagnostic methods for cancer
WO2018081648A2 (en) 2016-10-29 2018-05-03 Genentech, Inc. Anti-mic antibidies and methods of use
WO2018160841A1 (en) 2017-03-01 2018-09-07 Genentech, Inc. Diagnostic and therapeutic methods for cancer
WO2018189220A1 (en) 2017-04-13 2018-10-18 F. Hoffmann-La Roche Ag An interleukin-2 immunoconjugate, a cd40 agonist, and optionally a pd-1 axis binding antagonist for use in methods of treating cancer
EP3401335A1 (en) 2008-01-30 2018-11-14 Genentech, Inc. Composition comprising antibody that binds to domain ii of her2 and acidic variants thereof
WO2019018757A1 (en) 2017-07-21 2019-01-24 Genentech, Inc. THERAPEUTIC AND DIAGNOSTIC METHODS FOR CANCER
WO2019033043A2 (en) 2017-08-11 2019-02-14 Genentech, Inc. ANTI-CD8 ANTIBODIES AND USES THEREOF
WO2019051296A1 (en) 2017-09-08 2019-03-14 Genentech, Inc. DIAGNOSTIC AND THERAPEUTIC METHODS OF CANCER
US10240207B2 (en) 2014-03-24 2019-03-26 Genentech, Inc. Cancer treatment with c-met antagonists and correlation of the latter with HGF expression
WO2019084395A1 (en) 2017-10-27 2019-05-02 University Of Virginia Patent Foundation COMPOUNDS AND METHODS FOR REGULATING, LIMITING OR INHIBITING AVIL EXPRESSION
WO2019090263A1 (en) 2017-11-06 2019-05-09 Genentech, Inc. Diagnostic and therapeutic methods for cancer
WO2019136532A1 (en) 2018-01-15 2019-07-18 University Of Canberra Agents and methods for predicting response to therapy
WO2019165434A1 (en) 2018-02-26 2019-08-29 Genentech, Inc. Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies
WO2019186343A1 (en) 2018-03-26 2019-10-03 Novartis Ag N-(3-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)benzamide derivatives
WO2019186358A1 (en) 2018-03-26 2019-10-03 Novartis Ag 3-hydroxy-n-(3-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)pyrrolidine-1-carboxamide derivatives
WO2019226514A2 (en) 2018-05-21 2019-11-28 Nanostring Technologies, Inc. Molecular gene signatures and methods of using same
US10513498B2 (en) 2014-07-31 2019-12-24 Basf Se Process for preparing pyrazoles
WO2019246557A1 (en) 2018-06-23 2019-12-26 Genentech, Inc. Methods of treating lung cancer with a pd-1 axis binding antagonist, a platinum agent, and a topoisomerase ii inhibitor
WO2020018789A1 (en) 2018-07-18 2020-01-23 Genentech, Inc. Methods of treating lung cancer with a pd-1 axis binding antagonist, an antimetabolite, and a platinum agent
WO2020051099A1 (en) 2018-09-03 2020-03-12 Genentech, Inc. Carboxamide and sulfonamide derivatives useful as tead modulators
WO2020061060A1 (en) 2018-09-19 2020-03-26 Genentech, Inc. Therapeutic and diagnostic methods for bladder cancer
WO2020061349A1 (en) 2018-09-21 2020-03-26 Genentech, Inc. Diagnostic methods for triple-negative breast cancer
WO2020081767A1 (en) 2018-10-18 2020-04-23 Genentech, Inc. Diagnostic and therapeutic methods for sarcomatoid kidney cancer
WO2020131674A1 (en) 2018-12-19 2020-06-25 Array Biopharma Inc. 7-((3,5-dimethoxyphenyl)amino)quinoxaline derivatives as fgfr inhibitors for treating cancer
WO2020131627A1 (en) 2018-12-19 2020-06-25 Array Biopharma Inc. Substituted pyrazolo[1,5-a]pyridine compounds as inhibitors of fgfr tyrosine kinases
WO2020163589A1 (en) 2019-02-08 2020-08-13 Genentech, Inc. Diagnostic and therapeutic methods for cancer
WO2020176748A1 (en) 2019-02-27 2020-09-03 Genentech, Inc. Dosing for treatment with anti-tigit and anti-cd20 or anti-cd38 antibodies
WO2020172712A1 (en) 2019-02-27 2020-09-03 Epiaxis Therapeutics Pty Ltd Methods and agents for assessing t-cell function and predicting response to therapy
US10767232B2 (en) 2014-11-03 2020-09-08 Genentech, Inc. Methods and biomarkers for predicting efficacy and evaluation of an OX40 agonist treatment
WO2020223233A1 (en) 2019-04-30 2020-11-05 Genentech, Inc. Prognostic and therapeutic methods for colorectal cancer
WO2020226986A2 (en) 2019-05-03 2020-11-12 Genentech, Inc. Methods of treating cancer with an anti-pd-l1 antibody
WO2020231990A1 (en) * 2019-05-13 2020-11-19 Relay Therapeutics, Inc. Fgfr inhibitors and methods of use thereof
WO2021017892A1 (zh) 2019-07-26 2021-02-04 上海复宏汉霖生物技术股份有限公司 针对抗cd73抗体和变体的方法和组合物
EP3783029A1 (en) 2015-05-12 2021-02-24 F. Hoffmann-La Roche AG Therapeutic and diagnostic methods for cancer
WO2021046159A1 (en) 2019-09-04 2021-03-11 Genentech, Inc. Cd8 binding agents and uses thereof
WO2021062085A1 (en) 2019-09-27 2021-04-01 Genentech, Inc. Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies
WO2021083949A1 (en) 2019-10-29 2021-05-06 F. Hoffmann-La Roche Ag Bifunctional compounds for the treatment of cancer
WO2021092171A1 (en) 2019-11-06 2021-05-14 Genentech, Inc. Diagnostic and therapeutic methods for treatment of hematologic cancers
WO2021097110A1 (en) 2019-11-13 2021-05-20 Genentech, Inc. Therapeutic compounds and methods of use
WO2021119505A1 (en) 2019-12-13 2021-06-17 Genentech, Inc. Anti-ly6g6d antibodies and methods of use
WO2021127404A1 (en) 2019-12-20 2021-06-24 Erasca, Inc. Tricyclic pyridones and pyrimidones
WO2021154761A1 (en) 2020-01-27 2021-08-05 Genentech, Inc. Methods for treatment of cancer with an anti-tigit antagonist antibody
EP3862365A1 (en) 2016-01-08 2021-08-11 F. Hoffmann-La Roche AG Methods of treating cea-positive cancers using pd-1 axis binding antagonists and anti-cea/anti-cd3 bispecific antibodies
WO2021177980A1 (en) 2020-03-06 2021-09-10 Genentech, Inc. Combination therapy for cancer comprising pd-1 axis binding antagonist and il6 antagonist
WO2021194481A1 (en) 2020-03-24 2021-09-30 Genentech, Inc. Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies
WO2021202959A1 (en) 2020-04-03 2021-10-07 Genentech, Inc. Therapeutic and diagnostic methods for cancer
WO2021222167A1 (en) 2020-04-28 2021-11-04 Genentech, Inc. Methods and compositions for non-small cell lung cancer immunotherapy
WO2021257503A1 (en) 2020-06-16 2021-12-23 Genentech, Inc. Methods and compositions for treating triple-negative breast cancer
WO2021257124A1 (en) 2020-06-18 2021-12-23 Genentech, Inc. Treatment with anti-tigit antibodies and pd-1 axis binding antagonists
WO2022020716A1 (en) 2020-07-24 2022-01-27 Genentech, Inc. Heterocyclic inhibitors of tead for treating cancer
WO2022031749A1 (en) 2020-08-03 2022-02-10 Genentech, Inc. Diagnostic and therapeutic methods for lymphoma
WO2022036146A1 (en) 2020-08-12 2022-02-17 Genentech, Inc. Diagnostic and therapeutic methods for cancer
WO2022066805A1 (en) 2020-09-23 2022-03-31 Erasca, Inc. Tricyclic pyridones and pyrimidones
EP3978500A1 (en) 2015-12-16 2022-04-06 Genentech, Inc. Process for the preparation of tricyclic pi3k inhibitor compounds
WO2022072925A1 (en) 2020-10-02 2022-04-07 Mitokinin, Inc. Compositions and methods of treating kidney disease and fibrosis
WO2022076462A1 (en) 2020-10-05 2022-04-14 Genentech, Inc. Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
WO2022133345A1 (en) 2020-12-18 2022-06-23 Erasca, Inc. Tricyclic pyridones and pyrimidones
WO2022171745A1 (en) 2021-02-12 2022-08-18 F. Hoffmann-La Roche Ag Bicyclic tetrahydroazepine derivatives for the treatment of cancer
WO2022251296A1 (en) 2021-05-25 2022-12-01 Erasca, Inc. Sulfur-containing heteroaromatic tricyclic kras inhibitors
WO2022266206A1 (en) 2021-06-16 2022-12-22 Erasca, Inc. Kras inhibitor conjugates
US11547697B2 (en) 2009-08-17 2023-01-10 Millennium Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
WO2023018699A1 (en) 2021-08-10 2023-02-16 Erasca, Inc. Selective kras inhibitors
WO2023097195A1 (en) 2021-11-24 2023-06-01 Genentech, Inc. Therapeutic indazole compounds and methods of use in the treatment of cancer
WO2023097194A2 (en) 2021-11-24 2023-06-01 Genentech, Inc. Therapeutic compounds and methods of use
WO2023191816A1 (en) 2022-04-01 2023-10-05 Genentech, Inc. Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
WO2023219613A1 (en) 2022-05-11 2023-11-16 Genentech, Inc. Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
WO2023240058A2 (en) 2022-06-07 2023-12-14 Genentech, Inc. Prognostic and therapeutic methods for cancer
WO2024015897A1 (en) 2022-07-13 2024-01-18 Genentech, Inc. Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
WO2024020432A1 (en) 2022-07-19 2024-01-25 Genentech, Inc. Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
WO2024033388A1 (en) 2022-08-11 2024-02-15 F. Hoffmann-La Roche Ag Bicyclic tetrahydrothiazepine derivatives
WO2024033458A1 (en) 2022-08-11 2024-02-15 F. Hoffmann-La Roche Ag Bicyclic tetrahydroazepine derivatives
WO2024033389A1 (en) 2022-08-11 2024-02-15 F. Hoffmann-La Roche Ag Bicyclic tetrahydrothiazepine derivatives
WO2024033457A1 (en) 2022-08-11 2024-02-15 F. Hoffmann-La Roche Ag Bicyclic tetrahydrothiazepine derivatives
WO2024085242A2 (en) 2022-10-21 2024-04-25 Kawasaki Institute Of Industrial Promotion Non-fouling or super stealth vesicle
EP4360646A2 (en) 2015-09-25 2024-05-01 F. Hoffmann-La Roche AG Anti-tigit antibodies and methods of use
WO2024091991A1 (en) 2022-10-25 2024-05-02 Genentech, Inc. Therapeutic and diagnostic methods for multiple myeloma
WO2024173842A1 (en) 2023-02-17 2024-08-22 Erasca, Inc. Kras inhibitors
WO2024233341A1 (en) 2023-05-05 2024-11-14 Genentech, Inc. Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
US12152034B2 (en) 2020-11-18 2024-11-26 Relay Therapeutics, Inc. FGFR inhibitors and methods of making and using the same
WO2024254455A1 (en) 2023-06-08 2024-12-12 Genentech, Inc. Macrophage signatures for diagnostic and therapeutic methods for lymphoma
US12173005B1 (en) 2023-12-21 2024-12-24 King Faisal University Pyrimido[1′,6′:1,5]pyrazolo[4,3-b][1,7]naphthyridine compounds as CK2 inhibitors
WO2025024257A1 (en) 2023-07-21 2025-01-30 Genentech, Inc. Diagnostic and therapeutic methods for cancer
WO2025049277A1 (en) 2023-08-25 2025-03-06 Genentech, Inc. Methods and compositions for treating non-small cell lung cancer comprising an anti-tigit antagonist antibody and a pd-1 axis binding antagonist
US12324807B2 (en) 2018-06-01 2025-06-10 Cornell University Combination therapy for PI3K-associated disease or disorder
US12404540B2 (en) 2018-10-17 2025-09-02 The University Of Queensland Epigenetic biomarker and uses therefor
WO2026030464A1 (en) 2024-07-30 2026-02-05 Genentech, Inc. Dosage regimen for reducing cytokine release syndrome (crs) with anti-fcrh5/anti-cd3 bispecific antibodies in multiple myeloma therapy
WO2026030476A1 (en) 2024-07-30 2026-02-05 Genentech, Inc. Precision medicine for optimal dosage of combined therapies systems and methods of use thereof

Families Citing this family (335)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2109796T3 (es) * 1994-05-03 1998-01-16 Ciba Geigy Ag Derivados de pirrolopirimidilo con efecto antiproliferante.
TW321649B (pl) * 1994-11-12 1997-12-01 Zeneca Ltd
GB9424233D0 (en) * 1994-11-30 1995-01-18 Zeneca Ltd Quinazoline derivatives
DE69613367T2 (de) * 1995-04-27 2002-04-18 Astrazeneca Ab, Soedertaelje Chinazolin derivate
GB9508538D0 (en) * 1995-04-27 1995-06-14 Zeneca Ltd Quinazoline derivatives
GB9508565D0 (en) * 1995-04-27 1995-06-14 Zeneca Ltd Quiazoline derivative
GB9508537D0 (en) * 1995-04-27 1995-06-14 Zeneca Ltd Quinazoline derivatives
GB9508535D0 (en) * 1995-04-27 1995-06-14 Zeneca Ltd Quinazoline derivative
US6228871B1 (en) 1995-07-10 2001-05-08 Merck & Co., Inc. Angiogenesis inhibitors
GB9624482D0 (en) 1995-12-18 1997-01-15 Zeneca Phaema S A Chemical compounds
EP0888349B1 (en) * 1996-01-23 2002-05-22 Novartis AG Pyrrolopyrimidines and processes for their preparation
DK0880508T3 (da) 1996-02-13 2003-06-30 Astrazeneca Ab Quinazolinderivater som VEGF-inhibitorer
GB9603097D0 (en) * 1996-02-14 1996-04-10 Zeneca Ltd Quinazoline compounds
CN1116286C (zh) 1996-03-05 2003-07-30 曾尼卡有限公司 4－苯胺基喹唑啉衍生物
GB9607729D0 (en) * 1996-04-13 1996-06-19 Zeneca Ltd Quinazoline derivatives
GB9707800D0 (en) 1996-05-06 1997-06-04 Zeneca Ltd Chemical compounds
CA2262421C (en) 1996-08-23 2007-10-02 Novartis Ag Substituted pyrrolopyrimidines and processes for their preparation
ATE300521T1 (de) 1996-09-25 2005-08-15 Astrazeneca Ab Chinolin-derivate die den effekt von wachstumsfaktoren wie vegf vezögern
GB9718972D0 (en) 1996-09-25 1997-11-12 Zeneca Ltd Chemical compounds
JP4205168B2 (ja) 1996-10-02 2009-01-07 ノバルティス アクチエンゲゼルシヤフト ピリミジン誘導体およびその製造法
CN1246856A (zh) 1996-11-19 2000-03-08 安姆根有限公司 芳基和杂芳基取代的稠合吡咯抗炎药
US6413971B1 (en) * 1996-11-27 2002-07-02 Pfizer Inc Fused bicyclic pyrimidine derivatives
US7863444B2 (en) 1997-03-19 2011-01-04 Abbott Laboratories 4-aminopyrrolopyrimidines as kinase inhibitors
WO1998043973A1 (de) * 1997-03-27 1998-10-08 Novartis Ag Zwischenprodukte und verfahren zur herstellung von pyrimidinderivaten
US6235741B1 (en) 1997-05-30 2001-05-22 Merck & Co., Inc. Angiogenesis inhibitors
EP0889127A1 (en) * 1997-07-01 1999-01-07 Smithkline Beecham Corporation Serine/threonine protein kinase (H-SGK2)
ATE368665T1 (de) 1997-08-22 2007-08-15 Astrazeneca Ab Oxindolylchinazolinderivate als angiogenesehemmer
US6162804A (en) * 1997-09-26 2000-12-19 Merck & Co., Inc. Tyrosine kinase inhibitors
US6465484B1 (en) 1997-09-26 2002-10-15 Merck & Co., Inc. Angiogenesis inhibitors
US6380203B1 (en) 1998-01-14 2002-04-30 Merck & Co., Inc. Angiogenesis inhibitors
ATE496035T1 (de) 1998-03-31 2011-02-15 Kyowa Hakko Kirin Co Ltd Stickstoffenthaltende heterocyclische verbindungen
US6878716B1 (en) 1998-06-02 2005-04-12 Osi Pharmaceuticals, Inc. Compounds specific to adenosine A1 receptor and uses thereof
US6686366B1 (en) 1998-06-02 2004-02-03 Osi Pharmaceuticals, Inc. Compounds specific to adenosine A3 receptor and uses thereof
HUP0103836A3 (en) 1998-06-02 2003-05-28 Osi Pharmaceuticals Inc Uniond Pyrrolo[2,3d]pyrimidine compositions and their use
EP1087970B1 (en) 1998-06-19 2004-04-28 Pfizer Products Inc. PYRROLO 2,3-d]PYRIMIDINE COMPOUNDS
PA8474101A1 (es) 1998-06-19 2000-09-29 Pfizer Prod Inc Compuestos de pirrolo [2,3-d] pirimidina
US6017918A (en) * 1998-08-06 2000-01-25 Warner-Lambert Company Phenyl glycine compounds and methods of treating atherosclerosis and restenosis
US6284795B1 (en) * 1998-09-04 2001-09-04 Warner-Lambert Company Sulfonamide compounds and methods of treating atherosclerosis and restenosis
SK3852001A3 (en) * 1998-09-18 2003-03-04 Basf Ag 4-Aminopyrrolopyrimidines as kinase inhibitors
US6713474B2 (en) 1998-09-18 2004-03-30 Abbott Gmbh & Co. Kg Pyrrolopyrimidines as therapeutic agents
UA71945C2 (en) * 1999-01-27 2005-01-17 Pfizer Prod Inc Substituted bicyclic derivatives being used as anticancer agents
CA2375259C (en) 1999-06-21 2009-04-28 Boehringer Ingelheim Pharma Kg Bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and processes for preparing them
GB9925958D0 (en) * 1999-11-02 1999-12-29 Bundred Nigel J Therapeutic use
EP1676845B1 (en) 1999-11-05 2008-06-11 AstraZeneca AB New quinazoline derivatives
US6680322B2 (en) 1999-12-02 2004-01-20 Osi Pharmaceuticals, Inc. Compounds specific to adenosine A1 receptors and uses thereof
US7160890B2 (en) 1999-12-02 2007-01-09 Osi Pharmaceuticals, Inc. Compounds specific to adenosine A3 receptor and uses thereof
US6664252B2 (en) 1999-12-02 2003-12-16 Osi Pharmaceuticals, Inc. 4-aminopyrrolo[2,3-d]pyrimidine compounds specific to adenosine A2a receptor and uses thereof
KR100477818B1 (ko) 1999-12-10 2005-03-22 화이자 프로덕츠 인코포레이티드 피롤로[2,3-ｄ] 피리미딘 화합물
ES2267748T3 (es) 2000-04-07 2007-03-16 Astrazeneca Ab Compuestos de quinazolina.
HRP20021000A2 (en) 2000-06-26 2005-02-28 Pfizer Products Inc. PYRROLO[2,3-d]PYRIMIDINE COMPOUNDS AS IMMUNOSUPPRESSIVE AGENTS
EP1170011A1 (en) * 2000-07-06 2002-01-09 Boehringer Ingelheim International GmbH Novel use of inhibitors of the epidermal growth factor receptor
US7776315B2 (en) 2000-10-31 2010-08-17 Boehringer Ingelheim Pharma Gmbh & Co. Kg Pharmaceutical compositions based on anticholinergics and additional active ingredients
ES2290199T3 (es) * 2000-11-22 2008-02-16 Novartis Ag Mezcla que incluye un agente que reduce la actividad de fcve y un agente que reduce la actividad de fce.
US6673802B2 (en) 2000-12-01 2004-01-06 Osi Pharmaceuticals, Inc. Compounds specific to adenosine A3 receptor and uses thereof
US6680324B2 (en) 2000-12-01 2004-01-20 Osi Pharmaceuticals, Inc. Compounds specific to adenosine A1 receptors and uses thereof
US7019012B2 (en) 2000-12-20 2006-03-28 Boehringer Ingelheim International Pharma Gmbh & Co. Kg Quinazoline derivatives and pharmaceutical compositions containing them
DK3351246T3 (da) 2001-02-19 2019-06-03 Novartis Pharma Ag Rapamycinderivat til behandling af en solid tumor, som er associeret med dereguleret angionese
PL207197B1 (pl) * 2001-02-27 2010-11-30 Novartis Ag Połączenie obejmujące inhibitor przekazywania sygnału i pochodną epotylonową, kompozycja farmaceutyczna zawierająca to połączenie oraz zastosowanie połączenia
MXPA03010401A (es) 2001-05-16 2004-03-09 Novartis Ag Combinacion que comprende n-[5-[4- (4-metil- piperazino-metil) -benzoilamido] -2-metilfenil] -4-(3-piridil)-2 -pirimidin-amina, y un agente quimioterapeutico.
US7301023B2 (en) 2001-05-31 2007-11-27 Pfizer Inc. Chiral salt resolution
US7323469B2 (en) 2001-08-07 2008-01-29 Novartis Ag 7H-pyrrolo[2,3-d]pyrimidine derivatives
JP2005507424A (ja) * 2001-10-29 2005-03-17 ノバルティス アクチエンゲゼルシャフト 固形腫瘍の処置における７Ｈ−ピロロ［２，３−ｄ］ピリミジン誘導体の使用
DE60234118D1 (de) 2001-11-30 2009-12-03 Osi Pharm Inc Verbindungen, die für Adenosin A1 und A3 Rezeptoren spezifisch sind, und deren Anwendungen
ATE458483T1 (de) 2001-12-20 2010-03-15 Osi Pharm Inc Selektive pyrimidin-a2b-antagonistenverbindungen, ihre synthese und verwendung
US20030229067A1 (en) 2001-12-20 2003-12-11 Arlindo Castelhano Pyrrolopyrimidine A2b selective antagonist compounds, their synthesis and use
GB0206215D0 (en) 2002-03-15 2002-05-01 Novartis Ag Organic compounds
DE10221018A1 (de) 2002-05-11 2003-11-27 Boehringer Ingelheim Pharma Verwendung von Hemmern der EGFR-vermittelten Signaltransduktion zur Behandlung von gutartiger Prostatahyperplasie (BPH)/Prostatahypertrophie
CA2483594C (en) 2002-05-16 2011-02-15 Novartis Ag Use of edg receptor binding agents in cancer
CN1717236A (zh) 2002-11-26 2006-01-04 辉瑞产品公司 治疗移植排斥的方法
US7223749B2 (en) 2003-02-20 2007-05-29 Boehringer Ingelheim International Gmbh Bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and processes for preparing them
MY150088A (en) 2003-05-19 2013-11-29 Irm Llc Immunosuppressant compounds and compositions
MXPA05012461A (es) 2003-05-19 2006-02-22 Irm Llc Compuestos y composiciones inmunosupresores.
WO2005049829A1 (en) 2003-05-30 2005-06-02 Astrazeneca Uk Limited Process
CA2536954C (en) 2003-08-29 2012-11-27 Exelixis, Inc. C-kit modulators and methods of use
DE10349113A1 (de) 2003-10-17 2005-05-12 Boehringer Ingelheim Pharma Verfahren zur Herstellung von Aminocrotonylverbindungen
WO2005039588A2 (en) * 2003-10-22 2005-05-06 Novartis Ag Methods for determining the risk of developing liver and lung toxicity
CA2560162C (en) 2004-04-07 2013-05-21 Novartis Ag Inhibitors of iap
US8080577B2 (en) 2004-05-06 2011-12-20 Bioresponse, L.L.C. Diindolylmethane formulations for the treatment of leiomyomas
GB0512324D0 (en) 2005-06-16 2005-07-27 Novartis Ag Organic compounds
CA2572314A1 (en) 2004-06-29 2006-01-12 Christopher N. Farthing Pyrrolo[2,3-d]pyrimidines that modulate ack1 and lck activity
US20060035893A1 (en) 2004-08-07 2006-02-16 Boehringer Ingelheim International Gmbh Pharmaceutical compositions for treatment of respiratory and gastrointestinal disorders
PE20060777A1 (es) 2004-12-24 2006-10-06 Boehringer Ingelheim Int Derivados de indolinona para el tratamiento o la prevencion de enfermedades fibroticas
US7989486B2 (en) 2004-12-30 2011-08-02 Bioresponse, L.L.C. Use of diindolylmethane-related indoles for the treatment and prevention of respiratory syncytial virus associated conditions
CR9465A (es) * 2005-03-25 2008-06-19 Surface Logix Inc Compuestos mejorados farmacocineticamente
GB0510390D0 (en) 2005-05-20 2005-06-29 Novartis Ag Organic compounds
US20080227980A1 (en) * 2005-08-05 2008-09-18 Novartis Ag Preparation of a 7H-Pyrrolo [2,3-D] Pyrimidine Derivative
US8119655B2 (en) * 2005-10-07 2012-02-21 Takeda Pharmaceutical Company Limited Kinase inhibitors
JP5688877B2 (ja) 2005-11-11 2015-03-25 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 癌疾患の治療用キナゾリン誘導体
ES2481671T3 (es) 2005-11-21 2014-07-31 Novartis Ag Inhibidores de mTOR en el tratamiento de tumores endocrinos
PT2348023E (pt) 2005-12-13 2015-09-15 Incyte Corp Pirrolo[2,3-b] pirimidinas e pirrolo[2,3-b]piridinas substituídas com heteroarilo como inibidores de janus quinase
GB0605120D0 (en) 2006-03-14 2006-04-26 Novartis Ag Organic Compounds
CA2645633A1 (en) 2006-04-05 2007-11-01 Novartis Ag Combinations of therapeutic agents for treating cancer
CN101415424B (zh) 2006-04-05 2012-12-05 诺瓦提斯公司 用于治疗癌症、包含bcr-abl/c-kit/pdgf-r tk抑制剂的组合
RU2469721C2 (ru) 2006-05-09 2012-12-20 Новартис Аг Комбинация, включающая комплексон железа и противоопухолевый агент, и ее применение
KR20090074202A (ko) 2006-09-18 2009-07-06 베링거 인겔하임 인터내셔날 게엠베하 Ｅｇｆｒ 돌연변이를 갖는 암을 치료하는 방법
BRPI0717564A2 (pt) 2006-09-29 2013-10-22 Novartis Ag Pirazolopirimidinas como inibidores de pi3k lipídeo cinase
WO2008057253A2 (en) 2006-10-27 2008-05-15 Bioresponse, L.L.C. Anti-parasitic methods and compositions utilizing diindolylmethane-related indoles
JP2010519209A (ja) 2007-02-15 2010-06-03 ノバルティス アーゲー 癌を処置するためのｌｂｈ５８９と他の治療剤の組み合わせ剤
ES2714092T3 (es) 2007-06-13 2019-05-27 Incyte Holdings Corp Uso de sales del inhibidor de quinasas Janus (R)-3-(4-(7H-pirrolo[2,3-d]pirimidin-4-il)-1H-pirazol-1-il)-3-ciclopentilpropanonitrilo
CL2008001709A1 (es) 2007-06-13 2008-11-03 Incyte Corp Compuestos derivados de pirrolo [2,3-b]pirimidina, moduladores de quinasas jak; composicion farmaceutica; y uso en el tratamiento de enfermedades tales como cancer, psoriasis, artritis reumatoide, entre otras.
DE102007027800A1 (de) 2007-06-16 2008-12-18 Bayer Healthcare Ag Substituierte bicyclische Heteroaryl-Verbindungen und ihre Verwendung
US8618121B2 (en) 2007-07-02 2013-12-31 Cancer Research Technology Limited 9H-pyrimido[4,5-B]indoles, 9H-pyrido[4',3':4,5]pyrrolo[2,3-D]pyridines, and 9H 1,3,6,9 tetraaza-fluorenes as CHK1 kinase function inhibitors
SI2288610T1 (sl) 2008-03-11 2016-11-30 Incyte Holdings Corporation Derivati azetidina in ciklobutana kot inhibitorji jak
DE102008021699A1 (de) * 2008-04-25 2009-10-29 Schebo Biotech Ag Neue Pyrrolopyrimidin-Derivate und deren Verwendung
EP2268612B1 (en) 2008-03-24 2014-08-20 Novartis AG Arylsulfonamide-based matrix metalloprotease inhibitors
AU2009228778B2 (en) 2008-03-26 2012-04-19 Novartis Ag Hydroxamate-based inhibitors of deacetylases B
CA2733359C (en) 2008-08-20 2014-08-05 Pfizer Inc. Pyrrolo[2,3-d]pyrimidine compounds
WO2010043050A1 (en) 2008-10-16 2010-04-22 Celator Pharmaceuticals Corporation Combinations of a liposomal water-soluble camptothecin with cetuximab or bevacizumab
EP2349235A1 (en) 2008-11-07 2011-08-03 Triact Therapeutics, Inc. Use of catecholic butane derivatives in cancer therapy
JP5781934B2 (ja) * 2008-11-10 2015-09-24 ナショナル ヘルス リサーチ インスティテューツ チロシンキナーゼ阻害剤としての融合２環および３環ピリミジン化合物
ES2531831T3 (es) 2008-12-18 2015-03-20 Novartis Ag Forma polimórfica del ácido 1-(4-{1-[(E)-4-ciclohexil-3-trifluorometil-benciloxiimino]-etil}-2-etil-bencil)-azetidin-3-carboxilico
RS53041B (sr) 2008-12-18 2014-04-30 Novartis Ag Hemifumaratna so 1-[4-[1-(4-cikloheksil-3-trifluorometil-benziloksiimino)-etil]-2-etil-benzil]-azetidin-3-karboksilne kiseline
CN103204794A (zh) 2008-12-18 2013-07-17 诺瓦提斯公司 新的盐
WO2010083617A1 (en) 2009-01-21 2010-07-29 Oncalis Ag Pyrazolopyrimidines as protein kinase inhibitors
TW201031406A (en) 2009-01-29 2010-09-01 Novartis Ag Substituted benzimidazoles for the treatment of astrocytomas
EP2400985A2 (en) 2009-02-25 2012-01-04 OSI Pharmaceuticals, LLC Combination of an either an anti-igf-1r antibody or an igf binding protein and a small molecule igf-1r kinase inhibitor
US20110171124A1 (en) 2009-02-26 2011-07-14 Osi Pharmaceuticals, Inc. In situ methods for monitoring the EMT status of tumor cells in vivo
WO2010099138A2 (en) 2009-02-27 2010-09-02 Osi Pharmaceuticals, Inc. Methods for the identification of agents that inhibit mesenchymal-like tumor cells or their formation
JP2012519281A (ja) 2009-02-27 2012-08-23 オーエスアイ・ファーマシューティカルズ，エルエルシー 間葉様腫瘍細胞またはその生成を阻害する薬剤を同定するための方法
US8465912B2 (en) 2009-02-27 2013-06-18 OSI Pharmaceuticals, LLC Methods for the identification of agents that inhibit mesenchymal-like tumor cells or their formation
JP2012520893A (ja) 2009-03-18 2012-09-10 オーエスアイ・ファーマシューティカルズ，エルエルシー Ｅｇｆｒ阻害薬及びｉｇｆ−１ｒ阻害剤の投与を含む組み合わせ癌治療
ME03556B (me) 2009-05-22 2020-07-20 Incyte Holdings Corp 3-[4-(7h-pirolo[2,3-d]pirimidin-4-il)-1 h-pirazol-1-il]oktan- ili нертan - niтril kао јак inhibiтori
SG176130A1 (en) 2009-05-22 2011-12-29 Incyte Corp N-(HETERO)ARYL-PYRROLIDINE DERIVATIVES OF PYRAZOL-4-YL-PYRROLO[2,3-d]PYRIMIDINES AND PYRROL-3-YL-PYRROLO[2,3-d]PYRIMIDINES AS JANUS KINASE INHIBITORS
BRPI1015568B8 (pt) 2009-06-26 2021-05-25 Novartis Ag derivados de imidazolidin-2-ona 1,3-dissubstituídos como inibidores de cyp 17, seus usos, e composição farmacêutica
EP2451445B1 (en) 2009-07-06 2019-04-03 Boehringer Ingelheim International GmbH Process for drying of bibw2992, of its salts and of solid pharmaceutical formulations comprising this active ingredient
CA2768821A1 (en) * 2009-07-28 2011-02-03 Ube Industries, Ltd. Pyrrolo[2,3-d]pyrimidine derivative
US8389526B2 (en) 2009-08-07 2013-03-05 Novartis Ag 3-heteroarylmethyl-imidazo[1,2-b]pyridazin-6-yl derivatives
KR20120089643A (ko) 2009-08-12 2012-08-13 노파르티스 아게 헤테로시클릭 히드라존 화합물, 및 암 및 염증을 치료하기 위한 그의 용도
BR112012008061A2 (pt) 2009-08-20 2016-03-01 Novartis Ag compostos de oxima heterocíclica
CN102574785A (zh) 2009-08-26 2012-07-11 诺瓦提斯公司 四取代的杂芳基化合物和它们作为mdm2和/或mdm4调节剂的用途
AR078012A1 (es) 2009-09-01 2011-10-05 Incyte Corp Derivados heterociclicos de las pirazol-4-il- pirrolo (2,3-d) pirimidinas como inhibidores de la quinasa janus
CA2773661A1 (en) 2009-09-10 2011-03-17 Novartis Ag Ether derivatives of bicyclic heteroaryls
US8486902B2 (en) 2009-10-09 2013-07-16 Incyte Corporation Hydroxyl, keto, and glucuronide derivatives of 3-(4-(7H-pyrrolo[2,3-d] pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile
EP2496575B1 (en) 2009-11-04 2014-04-30 Novartis AG Heterocyclic sulfonamide derivatives useful as mek inhibitors
CA2780875A1 (en) 2009-11-13 2011-05-19 Pangaea Biotech, S.L. Molecular biomarkers for predicting response to tyrosine kinase inhibitors in lung cancer
JP6220126B2 (ja) 2009-11-23 2017-10-25 セルリアン・ファーマ・インコーポレイテッド 治療的送達のためのシクロデキストリンに基づく重合体
JP2013512215A (ja) 2009-11-25 2013-04-11 ノバルティス アーゲー 二環式ヘテロアリールのベンゼン縮合６員酸素含有ヘテロ環誘導体
WO2011070030A1 (en) 2009-12-08 2011-06-16 Novartis Ag Heterocyclic sulfonamide derivatives
CU24130B1 (es) 2009-12-22 2015-09-29 Novartis Ag Isoquinolinonas y quinazolinonas sustituidas
US8440693B2 (en) 2009-12-22 2013-05-14 Novartis Ag Substituted isoquinolinones and quinazolinones
WO2011090940A1 (en) 2010-01-19 2011-07-28 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutic delivery
TWI694826B (zh) 2010-03-10 2020-06-01 美商英塞特公司 作為ｊａｋ１抑制劑之哌啶-４-基三亞甲亞胺衍生物
WO2011119995A2 (en) 2010-03-26 2011-09-29 Cerulean Pharma Inc. Formulations and methods of use
EP2582680A1 (en) 2010-06-17 2013-04-24 Novartis AG Biphenyl substituted 1,3-dihydro-benzoimidazol-2-ylideneamine derivatives
EP2582681A1 (en) 2010-06-17 2013-04-24 Novartis AG Piperidinyl substituted 1,3-dihydro-benzoimidazol-2-ylideneamine derivatives
UA112517C2 (uk) 2010-07-06 2016-09-26 Новартіс Аг Тетрагідропіридопіримідинові похідні
JP2013537210A (ja) 2010-09-16 2013-09-30 ノバルティス アーゲー １７α−ヒドロキシラーゼ／Ｃ１７，２０−リアーゼ阻害剤
EP2640723A1 (en) 2010-11-19 2013-09-25 Incyte Corporation Cyclobutyl substituted pyrrolopyridine and pyrrolopyrimidine derivatives as jak inhibitors
CA2818545C (en) 2010-11-19 2019-04-16 Incyte Corporation Heterocyclic-substituted pyrrolopyridines and pyrrolopyrimidines as jak inhibitors
JP2014500308A (ja) 2010-12-21 2014-01-09 ノバルティス アーゲー Ｖｐｓ３４阻害剤としてのビヘテロアリール化合物
EP2468883A1 (en) 2010-12-22 2012-06-27 Pangaea Biotech S.L. Molecular biomarkers for predicting response to tyrosine kinase inhibitors in lung cancer
US9134297B2 (en) 2011-01-11 2015-09-15 Icahn School Of Medicine At Mount Sinai Method and compositions for treating cancer and related methods
EP2673277A1 (en) 2011-02-10 2013-12-18 Novartis AG [1, 2, 4]triazolo [4, 3 -b]pyridazine compounds as inhibitors of the c-met tyrosine kinase
JP5808826B2 (ja) 2011-02-23 2015-11-10 インテリカイン， エルエルシー 複素環化合物およびその使用
EP2492688A1 (en) 2011-02-23 2012-08-29 Pangaea Biotech, S.A. Molecular biomarkers for predicting response to antitumor treatment in lung cancer
CN103998040B (zh) 2011-03-04 2017-03-29 江苏康缘药业股份有限公司 炔基取代的喹唑啉化合物及其使用方法
JP2014507465A (ja) 2011-03-08 2014-03-27 ノバルティス アーゲー フルオロフェニル二環式ヘテロアリール化合物
PH12013501800A1 (en) * 2011-03-15 2013-10-14 L Livermore Nat Security Llc Tricyclic gyrase inhibitors
WO2012129145A1 (en) 2011-03-18 2012-09-27 OSI Pharmaceuticals, LLC Nscle combination therapy
JP2014519813A (ja) 2011-04-25 2014-08-21 オーエスアイ・ファーマシューティカルズ，エルエルシー 癌薬剤発見、診断、および治療におけるｅｍｔ遺伝子シグネチャーの使用
CA2834224A1 (en) 2011-04-28 2012-11-01 Novartis Ag 17.alpha.-hydroxylase/c17,20-lyase inhibitors
IN2014DN00123A (pl) 2011-06-09 2015-05-22 Novartis Ag
WO2012175520A1 (en) 2011-06-20 2012-12-27 Novartis Ag Hydroxy substituted isoquinolinone derivatives
EP2721007B1 (en) 2011-06-20 2015-04-29 Novartis AG Cyclohexyl isoquinolinone compounds
KR20140040819A (ko) 2011-06-20 2014-04-03 인사이트 코포레이션 Ｊａｋ 저해제로서의 아제티디닐 페닐, 피리딜 또는 피라지닐 카르복스아미드 유도체
PH12013502524A1 (en) 2011-06-27 2014-01-27 Novartis Ag Solid forms and salts of tetrahydro-pyrido-pyrimidine derivatives
CA2863679A1 (en) 2011-08-17 2014-05-30 Dennis Brown Compositions and methods to improve the therapeutic benefit of suboptimally administered chemical compounds including substituted hexitols such as dibromodulcitol
TW201313721A (zh) 2011-08-18 2013-04-01 Incyte Corp 作為ｊａｋ抑制劑之環己基氮雜環丁烷衍生物
WO2013033380A1 (en) 2011-08-31 2013-03-07 Genentech, Inc. Diagnostic markers
UA111854C2 (uk) 2011-09-07 2016-06-24 Інсайт Холдінгс Корпорейшн Способи і проміжні сполуки для отримання інгібіторів jak
WO2013038362A1 (en) 2011-09-15 2013-03-21 Novartis Ag 6 - substituted 3 - (quinolin- 6 - ylthio) - [1,2,4] triazolo [4, 3 -a] pyradines as tyrosine kinase
RU2014110228A (ru) 2011-09-30 2015-11-10 Дженентек, Инк. Диагностические маркеры
EP2776417B1 (en) 2011-11-09 2018-10-31 Cancer Research Technology Limited 5-(pyridin-2-yl-amino)-pyrazine-2-carbonitrile compounds and their therapeutic use
US8969341B2 (en) 2011-11-29 2015-03-03 Novartis Ag Pyrazolopyrrolidine compounds
US9408885B2 (en) 2011-12-01 2016-08-09 Vib Vzw Combinations of therapeutic agents for treating melanoma
PL2794600T3 (pl) 2011-12-22 2018-06-29 Novartis Ag Pochodne 2,3-dihydro-benzo[1,4]oksazyny i powiązane związki jako inhibitory kinazy fosfoinozytydu-3 (PI3K) do leczenia np. reumatoidalnego zapalenia stawów
EP2794594A1 (en) 2011-12-22 2014-10-29 Novartis AG Quinoline derivatives
US20130178520A1 (en) 2011-12-23 2013-07-11 Duke University Methods of treatment using arylcyclopropylamine compounds
JP2015503518A (ja) 2011-12-23 2015-02-02 ノバルティス アーゲー Ｂｃｌ２と結合相手の相互作用を阻害するための化合物
AU2012355613A1 (en) 2011-12-23 2014-07-17 Novartis Ag Compounds for inhibiting the interaction of BCL2 with binding partners
EA201491260A1 (ru) 2011-12-23 2014-11-28 Новартис Аг Соединения и композиции для ингибирования взаимодействия bcl2 с партнерами по связыванию
US20140357666A1 (en) 2011-12-23 2014-12-04 Novartis Ag Compounds for inhibiting the interaction of bcl2 with binding partners
KR20140107578A (ko) 2011-12-23 2014-09-04 노파르티스 아게 Bcl2와 결합 파트너의 상호작용을 억제하기 위한 화합물
US8815926B2 (en) 2012-01-26 2014-08-26 Novartis Ag Substituted pyrrolo[3,4-D]imidazoles for the treatment of MDM2/4 mediated diseases
SMT201900360T1 (it) 2012-01-27 2019-07-11 Univ Montreal DERIVATI DI PIRIMIDO[4,5-b]INDOLO E LORO UTILIZZO NELL'ESPANSIONE DELLE CELLULE STAMINALI EMATOPOIETICHE
EP2834246B1 (en) 2012-04-03 2021-07-28 Novartis AG Combination products with tyrosine kinase inhibitors and their use
WO2013152252A1 (en) 2012-04-06 2013-10-10 OSI Pharmaceuticals, LLC Combination anti-cancer therapy
AU2013261605B2 (en) 2012-05-15 2017-08-31 Cancer Research Technology Limited 5-[[4-[[morpholin-2-yl]methylamino]-5-(trifluoromethyl)-2-pyridyl]amino]pyrazine-2-carbonitrile and therapeutic uses thereof
US9193733B2 (en) 2012-05-18 2015-11-24 Incyte Holdings Corporation Piperidinylcyclobutyl substituted pyrrolopyridine and pyrrolopyrimidine derivatives as JAK inhibitors
JP6171003B2 (ja) 2012-05-24 2017-07-26 ノバルティス アーゲー ピロロピロリジノン化合物
EP2861256B1 (en) 2012-06-15 2019-10-23 The Brigham and Women's Hospital, Inc. Compositions for treating cancer and methods for making the same
WO2013190089A1 (en) 2012-06-21 2013-12-27 Pangaea Biotech, S.L. Molecular biomarkers for predicting outcome in lung cancer
WO2014025395A1 (en) 2012-08-06 2014-02-13 Duke University Compounds and methods for targeting hsp90
US20150284394A1 (en) * 2012-10-26 2015-10-08 Hoffmann-La Roche Inc. Inhibitors of bruton's tyrosine kinase
EP3919069A1 (en) 2012-11-05 2021-12-08 Dana-Farber Cancer Institute, Inc. Xbp1, cd138, and cs1 peptides, pharmaceutical compositions that include the peptides, and methods of using such peptides and compositions
KR20210037012A (ko) 2012-11-15 2021-04-05 인사이트 홀딩스 코포레이션 룩솔리티니브의 서방성 제형
TW201422625A (zh) 2012-11-26 2014-06-16 Novartis Ag 二氫－吡啶并－□衍生物之固體形式
US9403827B2 (en) 2013-01-22 2016-08-02 Novartis Ag Substituted purinone compounds
WO2014115080A1 (en) 2013-01-22 2014-07-31 Novartis Ag Pyrazolo[3,4-d]pyrimidinone compounds as inhibitors of the p53/mdm2 interaction
WO2014128612A1 (en) 2013-02-20 2014-08-28 Novartis Ag Quinazolin-4-one derivatives
AU2014218976B2 (en) 2013-02-20 2018-11-15 Novartis Ag Treatment of cancer using humanized anti-EGFRvIII chimeric antigen receptor
CA2941010A1 (en) 2013-02-26 2014-09-04 Triact Therapeutics, Inc. Cancer therapy
SI2964650T1 (sl) 2013-03-06 2019-05-31 Incyte Holdings Corporation Postopki in vmesne spojine za izdelavo inhibitorja JAK
WO2014151147A1 (en) 2013-03-15 2014-09-25 Intellikine, Llc Combination of kinase inhibitors and uses thereof
EP2976085A1 (en) 2013-03-21 2016-01-27 INSERM - Institut National de la Santé et de la Recherche Médicale Method and pharmaceutical composition for use in the treatment of chronic liver diseases associated with a low hepcidin expression
WO2014155268A2 (en) 2013-03-25 2014-10-02 Novartis Ag Fgf-r tyrosine kinase activity inhibitors - use in diseases associated with lack of or reduced snf5 activity
KR20160061911A (ko) 2013-04-08 2016-06-01 데니스 엠. 브라운 최적하 투여된 화학 화합물의 치료 효과
US20150018376A1 (en) 2013-05-17 2015-01-15 Novartis Ag Pyrimidin-4-yl)oxy)-1h-indole-1-carboxamide derivatives and use thereof
UY35675A (es) 2013-07-24 2015-02-27 Novartis Ag Derivados sustituidos de quinazolin-4-ona
EA201690357A1 (ru) 2013-08-07 2016-07-29 Инсайт Корпорейшн Лекарственные формы с замедленным высвобождением для ингибитора jak1
WO2015022663A1 (en) 2013-08-14 2015-02-19 Novartis Ag Compounds and compositions as inhibitors of mek
US9227969B2 (en) 2013-08-14 2016-01-05 Novartis Ag Compounds and compositions as inhibitors of MEK
WO2015022664A1 (en) 2013-08-14 2015-02-19 Novartis Ag Compounds and compositions as inhibitors of mek
US9381246B2 (en) 2013-09-09 2016-07-05 Triact Therapeutics, Inc. Cancer therapy
CA2920059A1 (en) 2013-09-22 2015-03-26 Calitor Sciences, Llc Substituted aminopyrimidine compounds and methods of use
TW201605450A (zh) 2013-12-03 2016-02-16 諾華公司 Ｍｄｍ２抑制劑與ＢＲＡＦ抑制劑之組合及其用途
US9242965B2 (en) 2013-12-31 2016-01-26 Boehringer Ingelheim International Gmbh Process for the manufacture of (E)-4-N,N-dialkylamino crotonic acid in HX salt form and use thereof for synthesis of EGFR tyrosine kinase inhibitors
US10000469B2 (en) 2014-03-25 2018-06-19 Duke University Heat shock protein 70 (hsp-70) receptor ligands
WO2015145388A2 (en) 2014-03-27 2015-10-01 Novartis Ag Methods of treating colorectal cancers harboring upstream wnt pathway mutations
US9394281B2 (en) 2014-03-28 2016-07-19 Calitor Sciences, Llc Substituted heteroaryl compounds and methods of use
CN106470681A (zh) 2014-04-03 2017-03-01 茵维特丝肿瘤学私营有限责任公司 超分子组合治疗药物
WO2015156674A2 (en) 2014-04-10 2015-10-15 Stichting Het Nederlands Kanker Instituut Method for treating cancer
US9498467B2 (en) 2014-05-30 2016-11-22 Incyte Corporation Treatment of chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML) by inhibitors of JAK1
WO2016011658A1 (en) 2014-07-25 2016-01-28 Novartis Ag Combination therapy
US10195208B2 (en) 2014-07-31 2019-02-05 Novartis Ag Combination therapy
MX394474B (es) 2014-12-24 2025-03-24 Genentech Inc Métodos de pronóstico para cáncer de vejiga sin invasión muscular y antagonistas para usarse en el tratamiento de lo mismo.
US10828329B2 (en) 2015-06-05 2020-11-10 Hema-Quebec Methods for culturing and/or differentiating hematopoietic stem cells into progenitors and uses thereof
FR3037959B1 (fr) 2015-06-23 2017-08-04 Servier Lab Nouveaux derives bicycliques, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
EP3347097B1 (en) 2015-09-11 2021-02-24 Sunshine Lake Pharma Co., Ltd. Substituted aminopyrimidine derivatives as modulators of the kinases jak, flt3 and aurora
US11261187B2 (en) 2016-04-22 2022-03-01 Duke University Compounds and methods for targeting HSP90
WO2018039203A1 (en) 2016-08-23 2018-03-01 Oncopep, Inc. Peptide vaccines and durvalumab for treating multiple myeloma
WO2018039205A1 (en) 2016-08-23 2018-03-01 Oncopep, Inc. Peptide vaccines and durvalumab for treating breast cancer
RU2019112860A (ru) 2016-09-27 2020-10-30 Серо Терапьютикс, Инк. Молекулы химерных интернализационных рецепторов
US10927083B2 (en) 2016-09-29 2021-02-23 Duke University Substituted benzimidazoles as inhibitors of transforming growth factor-β kinase
US10207998B2 (en) 2016-09-29 2019-02-19 Duke University Substituted benzimidazole and substituted benzothiazole inhibitors of transforming growth factor-β kinase and methods of use thereof
US10532042B2 (en) 2016-12-22 2020-01-14 Amgen Inc. KRAS G12C inhibitors and methods of using the same
JOP20190272A1 (ar) 2017-05-22 2019-11-21 Amgen Inc مثبطات kras g12c وطرق لاستخدامها
EP4403175A3 (en) 2017-09-08 2024-10-02 Amgen Inc. Inhibitors of kras g12c and methods of using the same
MX2020007266A (es) 2017-09-26 2020-09-07 Cero Therapeutics Inc Moleculas del receptor quimerico de engullido y metodos de uso.
EP3700575A1 (en) 2017-10-24 2020-09-02 Oncopep, Inc. Peptide vaccines and pembrolizumab for treating breast cancer
WO2019083960A1 (en) 2017-10-24 2019-05-02 Oncopep, Inc. PEPTIDE VACCINES AND HDAC INHIBITORS FOR THE TREATMENT OF MULTIPLE MYELOMA
EP3710006A4 (en) 2017-11-19 2021-09-01 Sunshine Lake Pharma Co., Ltd. SUBSTITUTED HETEROARYL COMPOUNDS AND METHOD OF USING
JP7021356B2 (ja) 2017-12-21 2022-02-16 ヘフェイ インスティテューツ オブ フィジカル サイエンス， チャイニーズ アカデミー オブ サイエンシーズ ピリミジン誘導体系キナーゼ阻害剤類
KR102737185B1 (ko) 2018-01-20 2024-12-05 선샤인 레이크 파르마 컴퍼니 리미티드 치환된 아미노피리미딘 화합물 및 이의 사용 방법
KR20210024443A (ko) 2018-03-28 2021-03-05 세로 테라퓨틱스, 인코포레이티드 세포 면역요법 조성물 및 이의 용도
EP3774906A1 (en) 2018-03-28 2021-02-17 Cero Therapeutics, Inc. Chimeric tim4 receptors and uses thereof
WO2019191339A1 (en) 2018-03-28 2019-10-03 Cero Therapeutics, Inc. Expression vectors for chimeric engulfment receptors, genetically modified host cells, and uses thereof
MA52501A (fr) 2018-05-04 2021-03-10 Amgen Inc Inhibiteurs de kras g12c et leurs procédés d'utilisation
JP7361722B2 (ja) 2018-05-04 2023-10-16 アムジエン・インコーポレーテツド Ｋｒａｓ ｇ１２ｃ阻害剤及び同一物の使用方法
EP3790886B1 (en) 2018-05-10 2024-06-26 Amgen Inc. Kras g12c inhibitors for the treatment of cancer
AU2019278998B2 (en) 2018-06-01 2023-11-09 Amgen Inc. KRAS G12C inhibitors and methods of using the same
JP7357644B2 (ja) 2018-06-11 2023-10-06 アムジエン・インコーポレーテツド がんを処置するためのｋｒａｓ ｇ１２ｃ阻害剤
EP3807276B1 (en) 2018-06-12 2025-12-10 Amgen Inc. Kras g12c inhibitors encompassing a piperazine ring and use thereof in the treatment of cancer
US12220423B2 (en) 2018-07-24 2025-02-11 Hygia Pharmaceuticals, Llc Compounds, derivatives, and analogs for cancer
US12491186B2 (en) 2018-10-04 2025-12-09 INSERM (Institut National de la Santé et de la Recherche Médicale) EGFR inhibitors for treating keratodermas
JP7516029B2 (ja) 2018-11-16 2024-07-16 アムジエン・インコーポレーテツド Ｋｒａｓ ｇ１２ｃ阻害剤化合物の重要な中間体の改良合成法
EP3883565A1 (en) 2018-11-19 2021-09-29 Amgen Inc. Kras g12c inhibitors and methods of using the same
JP7377679B2 (ja) 2018-11-19 2023-11-10 アムジエン・インコーポレーテツド がん治療のためのｋｒａｓｇ１２ｃ阻害剤及び１種以上の薬学的に活性な追加の薬剤を含む併用療法
US12459932B2 (en) 2018-12-20 2025-11-04 Amgen Inc. KIF18A inhibitors
ES2996960T3 (en) 2018-12-20 2025-02-13 Amgen Inc Heteroaryl amides useful as kif18a inhibitors
MA54547A (fr) 2018-12-20 2022-03-30 Amgen Inc Amides d'hétéroaryle utiles en tant qu'inhibiteurs de kif18a
IL283639B2 (en) 2018-12-20 2024-06-01 Amgen Inc Kif18a inhibitors
EP3897630B1 (en) 2018-12-21 2024-01-10 Celgene Corporation Thienopyridine inhibitors of ripk2
NL2022471B1 (en) 2019-01-29 2020-08-18 Vationpharma B V Solid state forms of oclacitinib
MX2021010323A (es) 2019-03-01 2021-12-10 Revolution Medicines Inc Compuestos bicíclicos de heterociclilo y usos de este.
WO2020180768A1 (en) 2019-03-01 2020-09-10 Revolution Medicines, Inc. Bicyclic heteroaryl compounds and uses thereof
EP3738593A1 (en) 2019-05-14 2020-11-18 Amgen, Inc Dosing of kras inhibitor for treatment of cancers
WO2020236947A1 (en) 2019-05-21 2020-11-26 Amgen Inc. Solid state forms
CA3147276A1 (en) 2019-08-02 2021-02-11 Amgen Inc. Kif18a inhibitors
WO2021026101A1 (en) 2019-08-02 2021-02-11 Amgen Inc. Kif18a inhibitors
MX2022001296A (es) 2019-08-02 2022-02-22 Amgen Inc Inhibidores de kif18a.
US20220289724A1 (en) 2019-08-02 2022-09-15 Amgen Inc. Kif18a inhibitors
US20240058446A1 (en) 2019-10-03 2024-02-22 Cero Therapeutics, Inc. Chimeric tim4 receptors and uses thereof
AU2020369569A1 (en) 2019-10-24 2022-04-14 Amgen Inc. Pyridopyrimidine derivatives useful as KRAS G12C and KRAS G12D inhibitors in the treatment of cancer
WO2021091982A1 (en) 2019-11-04 2021-05-14 Revolution Medicines, Inc. Ras inhibitors
CN115873020B (zh) 2019-11-04 2025-06-13 锐新医药公司 Ras抑制剂
CA3160142A1 (en) 2019-11-04 2021-05-14 Revolution Medicines, Inc. Ras inhibitors
PE20230249A1 (es) 2019-11-08 2023-02-07 Revolution Medicines Inc Compuestos de heteroarilo biciclicos y usos de estos
WO2021097256A1 (en) 2019-11-14 2021-05-20 Cohbar, Inc. Cxcr4 antagonist peptides
WO2021097207A1 (en) 2019-11-14 2021-05-20 Amgen Inc. Improved synthesis of kras g12c inhibitor compound
IL292315A (en) 2019-11-14 2022-06-01 Amgen Inc Improved synthesis of kras g12c inhibitor compound
EP4065231A1 (en) 2019-11-27 2022-10-05 Revolution Medicines, Inc. Covalent ras inhibitors and uses thereof
WO2021142026A1 (en) 2020-01-07 2021-07-15 Revolution Medicines, Inc. Shp2 inhibitor dosing and methods of treating cancer
WO2021233534A1 (en) 2020-05-20 2021-11-25 Pvac Medical Technologies Ltd Use of substance and pharmaceutical composition thereof, and medical treatments or uses thereof
WO2021185844A1 (en) 2020-03-16 2021-09-23 Pvac Medical Technologies Ltd Use of substance and pharmaceutical composition thereof, and medical treatments or uses thereof
US12359208B2 (en) 2020-04-15 2025-07-15 California Institute Of Technology Thermal control of T-cell immunotherapy through molecular and physical actuation
JP7747664B2 (ja) * 2020-05-20 2025-10-01 エフ． ホフマン－ラ ロシュ アーゲー 質量分析のためのベンジルピリジニウム試薬
US11833155B2 (en) 2020-06-03 2023-12-05 Incyte Corporation Combination therapy for treatment of myeloproliferative neoplasms
TW202214253A (zh) 2020-06-18 2022-04-16 美商銳新醫藥公司 延遲、預防及治療對ｒａｓ抑制劑之後天抗性之方法
US20230285576A1 (en) 2020-08-05 2023-09-14 Ellipses Pharma Ltd Treatment of cancer using a cyclodextrin-containing polymer-topoisomerase inhibitor conjugate and a parp inhibitor
WO2022036265A1 (en) 2020-08-14 2022-02-17 Cero Therapeutics, Inc. Chimeric tim receptors and uses thereof
WO2022036285A1 (en) 2020-08-14 2022-02-17 Cero Therapeutics, Inc. Compositions and methods for treating cancer with chimeric tim receptors in combination with inhibitors of poly (adp-ribose) polymerase
WO2022036287A1 (en) 2020-08-14 2022-02-17 Cero Therapeutics, Inc. Anti-cd72 chimeric receptors and uses thereof
WO2022047259A1 (en) 2020-08-28 2022-03-03 California Institute Of Technology Synthetic mammalian signaling circuits for robust cell population control
CN116209438A (zh) 2020-09-03 2023-06-02 锐新医药公司 使用sos1抑制剂治疗具有shp2突变的恶性疾病
JP7832184B2 (ja) 2020-09-15 2026-03-17 レヴォリューション・メディスンズ，インコーポレイテッド がんの治療における、ｒａｓ阻害剤としてのインドール誘導体
TW202237638A (zh) 2020-12-09 2022-10-01 日商武田藥品工業股份有限公司 烏苷酸環化酶ｃ（ｇｃｃ）抗原結合劑之組成物及其使用方法
AR124449A1 (es) 2020-12-22 2023-03-29 Qilu Regor Therapeutics Inc Inhibidores de sos1 y usos de los mismos
CN117203223A (zh) 2021-02-26 2023-12-08 凯洛尼亚疗法有限公司 淋巴细胞靶向慢病毒载体
PE20240088A1 (es) 2021-05-05 2024-01-16 Revolution Medicines Inc Inhibidores de ras
AR125787A1 (es) 2021-05-05 2023-08-16 Revolution Medicines Inc Inhibidores de ras
CN117500811A (zh) 2021-05-05 2024-02-02 锐新医药公司 共价ras抑制剂及其用途
JP2024529474A (ja) 2021-07-28 2024-08-06 セロ・セラピューティクス・インコーポレイテッド キメラＴｉｍ４受容体およびその使用
AR127308A1 (es) 2021-10-08 2024-01-10 Revolution Medicines Inc Inhibidores ras
WO2023114954A1 (en) 2021-12-17 2023-06-22 Genzyme Corporation Pyrazolopyrazine compounds as shp2 inhibitors
EP4227307A1 (en) 2022-02-11 2023-08-16 Genzyme Corporation Pyrazolopyrazine compounds as shp2 inhibitors
US20250188036A1 (en) 2022-03-07 2025-06-12 Amgen Inc. A process for preparing 4-methyl-2-propan-2-yl-pyridine-3-carbonitrile
EP4489755A1 (en) 2022-03-08 2025-01-15 Revolution Medicines, Inc. Methods for treating immune refractory lung cancer
WO2023186126A1 (zh) * 2022-03-31 2023-10-05 南京施江医药科技有限公司 一种芳香环类化合物及其用途
IL317476A (en) 2022-06-10 2025-02-01 Revolution Medicines Inc Macrocyclic RAS inhibitors
US20260041767A1 (en) 2022-08-02 2026-02-12 National University Corporation Hokkaido University Methods of improving cellular therapy with organelle complexes
WO2024041440A1 (en) * 2022-08-24 2024-02-29 Danatlas Pharmaceuticals Co., Ltd. Tricyclic heterocyclic derivatives, compositions and uses thereof
GB202215132D0 (en) * 2022-10-13 2022-11-30 Norwegian Univ Sci & Tech Ntnu Compound
GB202215117D0 (en) * 2022-10-13 2022-11-30 Norwegian Univ Sci & Tech Ntnu Compound
CR20250141A (es) 2022-10-14 2025-05-26 Black Diamond Therapeutics Inc Métodos de tratamiento del cáncer usando derivados de isoquinolina o 6-aza-quinolina
WO2024206858A1 (en) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions for inducing ras gtp hydrolysis and uses thereof
PE20252777A1 (es) 2023-04-07 2025-12-22 Revolution Medicines Inc Inhibidores macrociclicos de ras
PE20260039A1 (es) 2023-04-07 2026-01-09 Revolution Medicines Inc Inhibidores macrociclicos de ras
WO2024216016A1 (en) 2023-04-14 2024-10-17 Revolution Medicines, Inc. Crystalline forms of a ras inhibitor
KR20250169290A (ko) 2023-04-14 2025-12-02 레볼루션 메디슨즈, 인크. Ras 억제제의 결정형, 이를 함유하는 조성물 및 이의 사용 방법
EP4704850A1 (en) 2023-05-04 2026-03-11 Revolution Medicines, Inc. Combination therapy for a ras related disease or disorder
US20250049810A1 (en) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Methods of treating a ras protein-related disease or disorder
US11945823B1 (en) 2023-09-14 2024-04-02 King Faisal University Substituted pyrrolo[2,3-d]pyrimidines as CK2 inhibitors
US20250154171A1 (en) 2023-10-12 2025-05-15 Revolution Medicines, Inc. Ras inhibitors
WO2025137507A1 (en) 2023-12-22 2025-06-26 Regor Pharmaceuticals, Inc. Sos1 inhibitors and uses thereof
WO2025171296A1 (en) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Ras inhibitors
WO2025240847A1 (en) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Ras inhibitors
WO2025255438A1 (en) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Methods of treating a ras protein-related disease or disorder
WO2025265060A1 (en) 2024-06-21 2025-12-26 Revolution Medicines, Inc. Therapeutic compositions and methods for managing treatment-related effects
WO2026006747A1 (en) 2024-06-28 2026-01-02 Revolution Medicines, Inc. Ras inhibitors
WO2026015801A1 (en) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Methods of treating a ras related disease or disorder
WO2026015796A1 (en) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Methods of treating a ras related disease or disorder
WO2026015825A1 (en) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Use of ras inhibitor for treating pancreatic cancer
WO2026015790A1 (en) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Methods of treating a ras related disease or disorder
WO2026050446A1 (en) 2024-08-29 2026-03-05 Revolution Medicines, Inc. Ras inhibitors

Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3037980A (en) * 1955-08-18 1962-06-05 Burroughs Wellcome Co Pyrrolopyrimidine vasodilators and method of making them
DE3036390A1 (de) * 1980-09-26 1982-05-13 Troponwerke GmbH & Co KG, 5000 Köln Neue pyrrolo-pyrimidine, verfahren zu ihrer herstellung und ihre verwendung bei der herstellung von biologischen wirkstoffen
WO1992020642A1 (en) * 1991-05-10 1992-11-26 Rhone-Poulenc Rorer International (Holdings) Inc. Bis mono-and bicyclic aryl and heteroaryl compounds which inhibit egf and/or pdgf receptor tyrosine kinase
WO1995019774A1 (en) * 1994-01-25 1995-07-27 Warner-Lambert Company Bicyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family
WO1995019970A1 (en) * 1994-01-25 1995-07-27 Warner-Lambert Company Tricyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family
EP0682027A1 (de) * 1994-05-03 1995-11-15 Ciba-Geigy Ag Pyrrolopyrimidinderivate mit antiproliferativer Wirkung
WO1996010028A1 (en) * 1994-09-29 1996-04-04 Novartis Ag PYRROLO[2,3-d]PYRIMIDINES AND THEIR USE
WO1996031510A1 (en) * 1995-04-03 1996-10-10 Novartis Ag Pyrazole derivatives and processes for the preparation thereof
WO1996040142A1 (en) * 1995-06-07 1996-12-19 Pfizer Inc. Heterocyclic ring-fused pyrimidine derivatives
EP0773023A1 (en) * 1995-11-08 1997-05-14 Pfizer Inc. New uses for corticotropin releasing factor (CRF) antagonists
EP0795556A1 (en) * 1996-02-29 1997-09-17 PHARMACIA & UPJOHN S.p.A. 4-Substituted pyrrolopyrimidine compounds as tyrosin kinase inhibitors
US5674998A (en) * 1989-09-15 1997-10-07 Gensia Inc. C-4' modified adenosine kinase inhibitors
US5679683A (en) * 1994-01-25 1997-10-21 Warner-Lambert Company Tricyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family

Patent Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3037980A (en) * 1955-08-18 1962-06-05 Burroughs Wellcome Co Pyrrolopyrimidine vasodilators and method of making them
DE3036390A1 (de) * 1980-09-26 1982-05-13 Troponwerke GmbH & Co KG, 5000 Köln Neue pyrrolo-pyrimidine, verfahren zu ihrer herstellung und ihre verwendung bei der herstellung von biologischen wirkstoffen
US5674998A (en) * 1989-09-15 1997-10-07 Gensia Inc. C-4' modified adenosine kinase inhibitors
WO1992020642A1 (en) * 1991-05-10 1992-11-26 Rhone-Poulenc Rorer International (Holdings) Inc. Bis mono-and bicyclic aryl and heteroaryl compounds which inhibit egf and/or pdgf receptor tyrosine kinase
WO1995019774A1 (en) * 1994-01-25 1995-07-27 Warner-Lambert Company Bicyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family
WO1995019970A1 (en) * 1994-01-25 1995-07-27 Warner-Lambert Company Tricyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family
US5679683A (en) * 1994-01-25 1997-10-21 Warner-Lambert Company Tricyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family
EP0682027A1 (de) * 1994-05-03 1995-11-15 Ciba-Geigy Ag Pyrrolopyrimidinderivate mit antiproliferativer Wirkung
WO1996010028A1 (en) * 1994-09-29 1996-04-04 Novartis Ag PYRROLO[2,3-d]PYRIMIDINES AND THEIR USE
WO1996031510A1 (en) * 1995-04-03 1996-10-10 Novartis Ag Pyrazole derivatives and processes for the preparation thereof
WO1996040142A1 (en) * 1995-06-07 1996-12-19 Pfizer Inc. Heterocyclic ring-fused pyrimidine derivatives
EP0773023A1 (en) * 1995-11-08 1997-05-14 Pfizer Inc. New uses for corticotropin releasing factor (CRF) antagonists
EP0795556A1 (en) * 1996-02-29 1997-09-17 PHARMACIA & UPJOHN S.p.A. 4-Substituted pyrrolopyrimidine compounds as tyrosin kinase inhibitors

Non-Patent Citations (20)

* Cited by examiner, † Cited by third party
Title
A.J.Bridges et al., 86th Annual meeting of the Amer.Assoc.of Cancer Res. held Mar. 18 22 (1995). *
A.J.Bridges et al., 86th Annual meeting of the Amer.Assoc.of Cancer Res. held Mar. 18-22 (1995).
Derwent Abstract No. 92 213005/26 (1992). *
Derwent Abstract No. 92-213005/26 (1992).
J. Heterocyclic Chem., vol. 22, pp. 859 863 (1985). *
J. Heterocyclic Chem., vol. 22, pp. 859-863 (1985).
J.P. Marquet et al., Chimica Therapeutica, No. 6, pp. 427 438 (1971).* *
J.P. Marquet et al., Chimica Therapeutica, No. 6, pp. 427-438 (1971).*
L.Sun et al., 209th ACS meeting held Apr. 2 6 or 7 (1995). *
L.Sun et al., 209th ACS meeting held Apr. 2-6 or 7 (1995).
Liebigs Ann. Chem. pp. 142 148 (1985). *
Liebigs Ann. Chem. pp. 142-148 (1985).
Liebigs Ann. Chem. pp. 2066 2072 (1983). *
Liebigs Ann. Chem. pp. 2066-2072 (1983).
R.J. Mattson, et al., Synthesis, No. 3, pp. 217 218 (1979).* *
R.J. Mattson, et al., Synthesis, No. 3, pp. 217-218 (1979).*
R.L. Dow et al., 209th ACS meeting held Apr. 2 6 or 7 (1995). *
R.L. Dow et al., 209th ACS meeting held Apr. 2-6 or 7 (1995).
Traxler et al., "4-(Phenylamino)pyrrolopyrimidines: Potent and Selective, ATP Site Directed Inhibitors of the EGF-Receptor Protein Tyrosine Kinase," J. Med. Chem., vol. 39, pp. 2285-2292, Jun. 7, 1996.
Traxler et al., 4 (Phenylamino)pyrrolopyrimidines: Potent and Selective, ATP Site Directed Inhibitors of the EGF Receptor Protein Tyrosine Kinase, J. Med. Chem., vol. 39, pp. 2285 2292, Jun. 7, 1996. *

Cited By (213)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6395733B1 (en) * 1995-06-07 2002-05-28 Pfizer Inc Heterocyclic ring-fused pyrimidine derivatives
US20070161632A1 (en) * 2001-08-07 2007-07-12 Guido Bold 4-amino-6-phenyl-pyrrolo[2,3-d]pyrimidine derivatives
US20040242600A1 (en) * 2001-08-07 2004-12-02 Guido Bold 4-amino-6-phenyl-pyrrolo[2,3-d]pyrimidine derivatives
US7390805B2 (en) 2001-08-07 2008-06-24 Novartis Ag 4-amino-6-phenyl-pyrrolo[2,3-d]pyrimidine derivatives
US7244729B2 (en) * 2001-08-07 2007-07-17 Novartis Ag 4-amino-6-phenyl-pyrrolo[2,3-d]pyrimidine derivatives
WO2003030908A3 (en) * 2001-10-09 2003-11-06 Univ Cincinnati Inhibitors of the egf receptor for the treatment of thyroid cancer
US20040191254A1 (en) * 2001-10-09 2004-09-30 Fagin James Alexander Method of treatment of thyroid cancer
WO2003057149A3 (en) * 2001-12-28 2003-12-18 Bayer Ag 4-substituted fused heteropyrimidines and fused hetero-4-pyrimidones
US20040048887A1 (en) * 2002-07-09 2004-03-11 Boehringer Ingelheim Pharma Gmbh & Co. Kg Pharmaceutical compositions based on anticholinergics and EGFR kinase inhibitors
US20050165013A1 (en) * 2002-07-09 2005-07-28 Boehringer Ingelheim Pharma Gmbh & Co. Kg Pharmaceutical compositions containing anticholinergics and EGFR kinase inhibitors
US20050153989A1 (en) * 2004-01-13 2005-07-14 Ambit Biosciences Corporation Pyrrolopyrimidine derivatives and analogs and their use in the treatment and prevention of diseases
US20050239806A1 (en) * 2004-01-13 2005-10-27 Ambit Biosciences Corporation Pyrrolopyrimidine derivatives and analogs and their use in the treatment and prevention of diseases
US20050187389A1 (en) * 2004-01-13 2005-08-25 Ambit Biosciences Corporation Pyrrolopyrimidine derivatives and analogs and their use in the treatment and prevention of diseases
US20050165029A1 (en) * 2004-01-13 2005-07-28 Ambit Biosciences Corporation Pyrrolopyrimidine derivatives and analogs and their use in the treatment and prevention of diseases
US20090029973A1 (en) * 2004-06-02 2009-01-29 Takeda Pharmaceutical Company Limited Fused heterocyclic compound
US8178543B2 (en) 2004-06-02 2012-05-15 Takeda Pharmaceutical Company Limited Bi- and tricyclic fused pyrimidines as tyrosine kinase inhibitors
TWI392679B (zh) * 2004-06-02 2013-04-11 Takeda Pharmaceutical 稠合雜環化合物
US7465726B2 (en) 2004-08-02 2008-12-16 Osi Pharmaceuticals, Inc. Substituted pyrrolo[2.3-B]pyridines
US20060211678A1 (en) * 2004-08-02 2006-09-21 Saleh Ahmed Aryl-amino substituted pyrrolopyrimidine multi-kinase inhibiting compounds
US20090155247A1 (en) * 2005-02-18 2009-06-18 Ashkenazi Avi J Methods of Using Death Receptor Agonists and EGFR Inhibitors
US20080221132A1 (en) * 2006-09-11 2008-09-11 Xiong Cai Multi-Functional Small Molecules as Anti-Proliferative Agents
US20080161320A1 (en) * 2006-09-11 2008-07-03 Xiong Cai Fused bicyclic pyrimidines as ptk inhibitors containing a zinc binding moiety
EP2386655A2 (en) 2006-09-12 2011-11-16 Genentech, Inc. Methods and compositions for the diagnosis and treatment of lung cancer using KIT or KDG gene as genetic marker
EP2845912A1 (en) 2006-09-12 2015-03-11 Genentech, Inc. Methods and compositions for the diagnosis and treatment of lung cancer using KIT gene as genetic marker
US20110053991A1 (en) * 2007-11-19 2011-03-03 Gore Lia Treatment of Histone Deacetylase Mediated Disorders
WO2009098715A2 (en) 2008-01-11 2009-08-13 Natco Pharma Limited Novel pyrazolo [3, 4 -d] pyrimidine derivatives as anti -cancer agents
EP3401335A1 (en) 2008-01-30 2018-11-14 Genentech, Inc. Composition comprising antibody that binds to domain ii of her2 and acidic variants thereof
EP4119583A1 (en) 2008-01-30 2023-01-18 Genentech, Inc. Composition comprising antibody that binds to domain ii of her2 and acidic variants thereof
WO2010108127A1 (en) 2009-03-20 2010-09-23 Genentech, Inc. Bispecific anti-her antibodies
EP3088420A1 (en) 2009-03-20 2016-11-02 F. Hoffmann-La Roche AG Bispecific anti-her antibodies
US11547697B2 (en) 2009-08-17 2023-01-10 Millennium Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
WO2011060246A2 (en) 2009-11-12 2011-05-19 Genentech, Inc. A method of promoting dendritic spine density
WO2011086053A1 (en) 2010-01-12 2011-07-21 F. Hoffmann-La Roche Ag Tricyclic heterocyclic compounds, compositions and methods of use thereof
WO2011103242A1 (en) 2010-02-18 2011-08-25 Genentech, Inc. Neuregulin antagonists and use thereof in treating cancer
WO2011113802A2 (en) 2010-03-17 2011-09-22 F. Hoffmann-La Roche Ag Imidazopyridine compounds, compositions and methods of use
WO2011130654A1 (en) 2010-04-16 2011-10-20 Genentech, Inc. Fox03a as predictive biomarker for pi3k/akt kinase pathway inhibitor efficacy
WO2012031027A1 (en) 2010-08-31 2012-03-08 Genentech, Inc. Biomarkers and methods of treatment
EP3264089A1 (en) 2010-08-31 2018-01-03 Genentech, Inc. Biomarkers and methods of treatment
WO2012035039A1 (en) 2010-09-15 2012-03-22 F. Hoffmann-La Roche Ag Azabenzothiazole compounds, compositions and methods of use
WO2012066061A1 (en) 2010-11-19 2012-05-24 F. Hoffmann-La Roche Ag Pyrazolopyridines and pyrazolopyridines and their use as tyk2 inhibitors
WO2012085176A1 (en) 2010-12-23 2012-06-28 F. Hoffmann-La Roche Ag Tricyclic pyrazinone compounds, compositions and methods of use thereof as janus kinase inhibitors
WO2013007765A1 (en) 2011-07-13 2013-01-17 F. Hoffmann-La Roche Ag Fused tricyclic compounds for use as inhibitors of janus kinases
WO2013007768A1 (en) 2011-07-13 2013-01-17 F. Hoffmann-La Roche Ag Tricyclic heterocyclic compounds, compositions and methods of use thereof as jak inhibitors
WO2013024011A1 (en) 2011-08-12 2013-02-21 F. Hoffmann-La Roche Ag Indazole compounds, compositions and methods of use
WO2013025853A1 (en) 2011-08-17 2013-02-21 Genentech, Inc. Neuregulin antibodies and uses thereof
WO2013041539A1 (en) 2011-09-20 2013-03-28 F. Hoffmann-La Roche Ag Imidazopyridine compounds, compositions and methods of use
WO2013081645A2 (en) 2011-11-30 2013-06-06 Genentech, Inc. Erbb3 mutations in cancer
WO2013148315A1 (en) 2012-03-27 2013-10-03 Genentech, Inc. Diagnosis and treatments relating to her3 inhibitors
CN102936251A (zh) * 2012-11-05 2013-02-20 上海毕得医药科技有限公司 一种吡咯并[2,3-d]嘧啶衍生物的制备方法
WO2014128235A1 (en) 2013-02-22 2014-08-28 F. Hoffmann-La Roche Ag Methods of treating cancer and preventing drug resistance
WO2014138364A2 (en) 2013-03-06 2014-09-12 Genentech, Inc. Methods of treating and preventing cancer drug resistance
WO2014139326A1 (en) 2013-03-13 2014-09-18 Genentech, Inc. Pyrazolo compounds and uses thereof
WO2014152358A2 (en) 2013-03-14 2014-09-25 Genentech, Inc. Combinations of a mek inhibitor compound with an her3/egfr inhibitor compound and methods of use
WO2014153030A2 (en) 2013-03-14 2014-09-25 Genentech, Inc. Methods of treating cancer and preventing cancer drug resistance
WO2014144850A1 (en) 2013-03-15 2014-09-18 Genentech, Inc. Methods of treating cancer and preventing cancer drug resistance
WO2015035062A1 (en) 2013-09-05 2015-03-12 Genentech, Inc. Antiproliferative compounds
WO2015049325A1 (en) 2013-10-03 2015-04-09 F. Hoffmann-La Roche Ag Therapeutic inhibitors of cdk8 and uses thereof
WO2015058132A2 (en) 2013-10-18 2015-04-23 Genentech, Inc. Anti-rspo antibodies and methods of use
WO2015095418A1 (en) 2013-12-17 2015-06-25 Genentech, Inc. Methods of treating her2-positive cancers using pd-1 axis binding antagonists and anti-her2 antibodies
EP3527587A1 (en) 2013-12-17 2019-08-21 F. Hoffmann-La Roche AG Combination therapy comprising ox40 binding agonists and pd-l1 binding antagonists
WO2015095423A2 (en) 2013-12-17 2015-06-25 Genentech, Inc. Combination therapy comprising ox40 binding agonists and pd-1 axis binding antagonists
EP3680254A1 (en) 2013-12-17 2020-07-15 F. Hoffmann-La Roche AG Methods of treating her2-positive cancers using pd-1 axis binding antagonists and anti-her2 antibodies
EP3647324A1 (en) 2013-12-17 2020-05-06 F. Hoffmann-La Roche AG Methods of treating cancers using pd-1 axis binding antagonists and taxanes
US10240207B2 (en) 2014-03-24 2019-03-26 Genentech, Inc. Cancer treatment with c-met antagonists and correlation of the latter with HGF expression
WO2015153514A1 (en) 2014-03-31 2015-10-08 Genentech, Inc. Combination therapy comprising anti-angiogenesis agents and ox40 binding agonists
US9975957B2 (en) 2014-03-31 2018-05-22 Genentech, Inc. Anti-OX40 antibodies and methods of use
WO2015153513A1 (en) 2014-03-31 2015-10-08 Genentech, Inc. Anti-ox40 antibodies and methods of use
US10730951B2 (en) 2014-03-31 2020-08-04 Genentech, Inc. Anti-OX40 antibodies and methods of use
EP3632934A1 (en) 2014-03-31 2020-04-08 F. Hoffmann-La Roche AG Anti-ox40 antibodies and methods of use
US10513498B2 (en) 2014-07-31 2019-12-24 Basf Se Process for preparing pyrazoles
WO2016036873A1 (en) 2014-09-05 2016-03-10 Genentech, Inc. Therapeutic compounds and uses thereof
WO2016044694A1 (en) 2014-09-19 2016-03-24 Genentech, Inc. Use of cbp/ep300 and bet inhibitors for treatment of cancer
WO2016057924A1 (en) 2014-10-10 2016-04-14 Genentech, Inc. Pyrrolidine amide compounds as histone demethylase inhibitors
US10767232B2 (en) 2014-11-03 2020-09-08 Genentech, Inc. Methods and biomarkers for predicting efficacy and evaluation of an OX40 agonist treatment
US10845364B2 (en) 2014-11-03 2020-11-24 Genentech, Inc. Assays for detecting T cell immune subsets and methods of use thereof
WO2016073378A1 (en) 2014-11-03 2016-05-12 Genentech, Inc. Assays for detecting t cell immune subsets and methods of use thereof
WO2016073282A1 (en) 2014-11-06 2016-05-12 Genentech, Inc. Combination therapy comprising ox40 binding agonists and tigit inhibitors
WO2016077380A1 (en) 2014-11-10 2016-05-19 Genentech, Inc. Substituted pyrrolopyridines as inhibitors of bromodomain
WO2016077375A1 (en) 2014-11-10 2016-05-19 Genentech, Inc. Bromodomain inhibitors and uses thereof
WO2016077378A1 (en) 2014-11-10 2016-05-19 Genentech, Inc. Substituted pyrrolopyrdines as inhibitors of bromodomain
WO2016081384A1 (en) 2014-11-17 2016-05-26 Genentech, Inc. Combination therapy comprising ox40 binding agonists and pd-1 axis binding antagonists
EP3632915A1 (en) 2014-11-27 2020-04-08 Genentech, Inc. 4,5,6,7-tetrahydro-1 h-pyrazolo[4,3-c]pyridin-3-amine compounds as cbp and/or ep300 inhibitors
WO2016086200A1 (en) 2014-11-27 2016-06-02 Genentech, Inc. 4,5,6,7-tetrahydro-1 h-pyrazolo[4,3-c]pyridin-3-amine compounds as cbp and/or ep300 inhibitors
WO2016106340A2 (en) 2014-12-23 2016-06-30 Genentech, Inc. Compositions and methods for treating and diagnosing chemotherapy-resistant cancers
WO2016109546A2 (en) 2014-12-30 2016-07-07 Genentech, Inc. Methods and compositions for prognosis and treatment of cancers
WO2016112251A1 (en) 2015-01-09 2016-07-14 Genentech, Inc. 4,5-dihydroimidazole derivatives and their use as histone demethylase (kdm2b) inhibitors
WO2016112284A1 (en) 2015-01-09 2016-07-14 Genentech, Inc. (piperidin-3-yl)(naphthalen-2-yl)methanone derivatives and related compounds as inhibitors of the histone demethylase kdm2b for the treatment of cancer
WO2016112298A1 (en) 2015-01-09 2016-07-14 Genentech, Inc. Pyridazinone derivatives and their use in the treatment of cancer
WO2016123391A1 (en) 2015-01-29 2016-08-04 Genentech, Inc. Therapeutic compounds and uses thereof
WO2016123387A1 (en) 2015-01-30 2016-08-04 Genentech, Inc. Therapeutic compounds and uses thereof
WO2016138114A1 (en) 2015-02-25 2016-09-01 Genentech, Inc. Therapeutic pyridazine compounds and uses thereof
US10865248B2 (en) 2015-04-07 2020-12-15 Genentech, Inc. Antigen binding complex having agonistic activity and methods of use
WO2016164480A1 (en) 2015-04-07 2016-10-13 Genentech, Inc. Antigen binding complex having agonistic activity and methods of use
US10584102B2 (en) * 2015-05-11 2020-03-10 Basf Se Process for preparing 4-amino-pyridazines
US12162841B2 (en) 2015-05-11 2024-12-10 Basf Se Process for preparing 4-amino-pyridazines
CN107592859A (zh) * 2015-05-11 2018-01-16 巴斯夫欧洲公司 制备4‑氨基哒嗪类的方法
US11046656B2 (en) 2015-05-11 2021-06-29 Basf Se Process for preparing 4-amino-pyridazines
EP3783029A1 (en) 2015-05-12 2021-02-24 F. Hoffmann-La Roche AG Therapeutic and diagnostic methods for cancer
WO2016196298A1 (en) 2015-05-29 2016-12-08 Genentech, Inc. Therapeutic and diagnolstic methods for cancer
EP3708681A1 (en) 2015-05-29 2020-09-16 F. Hoffmann-La Roche AG Therapeutic and diagnostic methods for cancer
EP4335931A2 (en) 2015-05-29 2024-03-13 F. Hoffmann-La Roche AG Therapeutic and diagnostic methods for cancer
WO2016200835A1 (en) 2015-06-08 2016-12-15 Genentech, Inc. Methods of treating cancer using anti-ox40 antibodies and pd-1 axis binding antagonists
WO2016200836A1 (en) 2015-06-08 2016-12-15 Genentech, Inc. Methods of treating cancer using anti-ox40 antibodies
WO2016205320A1 (en) 2015-06-17 2016-12-22 Genentech, Inc. Methods of treating locally advanced or metastatic breast cancers using pd-1 axis binding antagonists and taxanes
WO2017033019A1 (en) 2015-08-26 2017-03-02 Fundación Centro Nacional De Investigaciones Oncológicas Carlos Iii (Cnio) Condensed tricyclic compounds as protein kinase inhibitors
EP4360646A2 (en) 2015-09-25 2024-05-01 F. Hoffmann-La Roche AG Anti-tigit antibodies and methods of use
EP3978500A1 (en) 2015-12-16 2022-04-06 Genentech, Inc. Process for the preparation of tricyclic pi3k inhibitor compounds
EP3862365A1 (en) 2016-01-08 2021-08-11 F. Hoffmann-La Roche AG Methods of treating cea-positive cancers using pd-1 axis binding antagonists and anti-cea/anti-cd3 bispecific antibodies
WO2017151502A1 (en) 2016-02-29 2017-09-08 Genentech, Inc. Therapeutic and diagnostic methods for cancer
EP4155415A1 (en) 2016-02-29 2023-03-29 Genentech, Inc. Therapeutic and diagnostic methods for cancer
EP3865511A1 (en) 2016-04-14 2021-08-18 F. Hoffmann-La Roche AG Anti-rspo3 antibodies and methods of use
WO2017180864A1 (en) 2016-04-14 2017-10-19 Genentech, Inc. Anti-rspo3 antibodies and methods of use
WO2017181079A2 (en) 2016-04-15 2017-10-19 Genentech, Inc. Methods for monitoring and treating cancer
WO2017180581A1 (en) 2016-04-15 2017-10-19 Genentech, Inc. Diagnostic and therapeutic methods for cancer
WO2017181111A2 (en) 2016-04-15 2017-10-19 Genentech, Inc. Methods for monitoring and treating cancer
WO2017205538A1 (en) 2016-05-24 2017-11-30 Genentech, Inc. Pyrazolopyridine derivatives for the treatment of cancer
EP4067347A1 (en) 2016-05-24 2022-10-05 Genentech, Inc. Heterocyclic inhibitors of cbp/ep300 for the treatment of cancer
WO2017205536A2 (en) 2016-05-24 2017-11-30 Genentech, Inc. Therapeutic compounds and uses thereof
WO2017214373A1 (en) 2016-06-08 2017-12-14 Genentech, Inc. Diagnostic and therapeutic methods for cancer
WO2018027204A1 (en) 2016-08-05 2018-02-08 Genentech, Inc. Multivalent and multiepitopic anitibodies having agonistic activity and methods of use
US11046776B2 (en) 2016-08-05 2021-06-29 Genentech, Inc. Multivalent and multiepitopic antibodies having agonistic activity and methods of use
WO2018029124A1 (en) 2016-08-08 2018-02-15 F. Hoffmann-La Roche Ag Therapeutic and diagnostic methods for cancer
WO2018068028A1 (en) 2016-10-06 2018-04-12 Genentech, Inc. Therapeutic and diagnostic methods for cancer
WO2018081648A2 (en) 2016-10-29 2018-05-03 Genentech, Inc. Anti-mic antibidies and methods of use
WO2018160841A1 (en) 2017-03-01 2018-09-07 Genentech, Inc. Diagnostic and therapeutic methods for cancer
WO2018189220A1 (en) 2017-04-13 2018-10-18 F. Hoffmann-La Roche Ag An interleukin-2 immunoconjugate, a cd40 agonist, and optionally a pd-1 axis binding antagonist for use in methods of treating cancer
WO2019018757A1 (en) 2017-07-21 2019-01-24 Genentech, Inc. THERAPEUTIC AND DIAGNOSTIC METHODS FOR CANCER
WO2019033043A2 (en) 2017-08-11 2019-02-14 Genentech, Inc. ANTI-CD8 ANTIBODIES AND USES THEREOF
WO2019051296A1 (en) 2017-09-08 2019-03-14 Genentech, Inc. DIAGNOSTIC AND THERAPEUTIC METHODS OF CANCER
WO2019084395A1 (en) 2017-10-27 2019-05-02 University Of Virginia Patent Foundation COMPOUNDS AND METHODS FOR REGULATING, LIMITING OR INHIBITING AVIL EXPRESSION
WO2019090263A1 (en) 2017-11-06 2019-05-09 Genentech, Inc. Diagnostic and therapeutic methods for cancer
WO2019136532A1 (en) 2018-01-15 2019-07-18 University Of Canberra Agents and methods for predicting response to therapy
WO2019165434A1 (en) 2018-02-26 2019-08-29 Genentech, Inc. Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies
WO2019186343A1 (en) 2018-03-26 2019-10-03 Novartis Ag N-(3-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)benzamide derivatives
WO2019186358A1 (en) 2018-03-26 2019-10-03 Novartis Ag 3-hydroxy-n-(3-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)pyrrolidine-1-carboxamide derivatives
EP4467549A2 (en) 2018-03-26 2024-11-27 Novartis AG Intermediates of n-(3-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)benzamide derivatives
EP4166557A1 (en) 2018-03-26 2023-04-19 Novartis AG Intermediates of n-(3-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)benzamide derivatives
WO2019226514A2 (en) 2018-05-21 2019-11-28 Nanostring Technologies, Inc. Molecular gene signatures and methods of using same
US12324807B2 (en) 2018-06-01 2025-06-10 Cornell University Combination therapy for PI3K-associated disease or disorder
WO2019246557A1 (en) 2018-06-23 2019-12-26 Genentech, Inc. Methods of treating lung cancer with a pd-1 axis binding antagonist, a platinum agent, and a topoisomerase ii inhibitor
WO2020018789A1 (en) 2018-07-18 2020-01-23 Genentech, Inc. Methods of treating lung cancer with a pd-1 axis binding antagonist, an antimetabolite, and a platinum agent
WO2020051099A1 (en) 2018-09-03 2020-03-12 Genentech, Inc. Carboxamide and sulfonamide derivatives useful as tead modulators
WO2020061060A1 (en) 2018-09-19 2020-03-26 Genentech, Inc. Therapeutic and diagnostic methods for bladder cancer
EP4249917A2 (en) 2018-09-21 2023-09-27 F. Hoffmann-La Roche AG Diagnostic methods for triple-negative breast cancer
WO2020061349A1 (en) 2018-09-21 2020-03-26 Genentech, Inc. Diagnostic methods for triple-negative breast cancer
US12404540B2 (en) 2018-10-17 2025-09-02 The University Of Queensland Epigenetic biomarker and uses therefor
WO2020081767A1 (en) 2018-10-18 2020-04-23 Genentech, Inc. Diagnostic and therapeutic methods for sarcomatoid kidney cancer
WO2020131627A1 (en) 2018-12-19 2020-06-25 Array Biopharma Inc. Substituted pyrazolo[1,5-a]pyridine compounds as inhibitors of fgfr tyrosine kinases
WO2020131674A1 (en) 2018-12-19 2020-06-25 Array Biopharma Inc. 7-((3,5-dimethoxyphenyl)amino)quinoxaline derivatives as fgfr inhibitors for treating cancer
WO2020163589A1 (en) 2019-02-08 2020-08-13 Genentech, Inc. Diagnostic and therapeutic methods for cancer
WO2020172712A1 (en) 2019-02-27 2020-09-03 Epiaxis Therapeutics Pty Ltd Methods and agents for assessing t-cell function and predicting response to therapy
WO2020176748A1 (en) 2019-02-27 2020-09-03 Genentech, Inc. Dosing for treatment with anti-tigit and anti-cd20 or anti-cd38 antibodies
WO2020223233A1 (en) 2019-04-30 2020-11-05 Genentech, Inc. Prognostic and therapeutic methods for colorectal cancer
WO2020226986A2 (en) 2019-05-03 2020-11-12 Genentech, Inc. Methods of treating cancer with an anti-pd-l1 antibody
US11780845B2 (en) 2019-05-13 2023-10-10 Relay Therapeutics, Inc. FGFR inhibitors and methods of use thereof
US12522605B2 (en) 2019-05-13 2026-01-13 Relay Therapeutics, Inc. FGFR inhibitors and methods of use thereof
AU2020274083B9 (en) * 2019-05-13 2025-05-01 D.E. Shaw Research, Llc FGFR inhibitors and methods of use thereof
AU2020274083B2 (en) * 2019-05-13 2025-04-24 D.E. Shaw Research, Llc FGFR inhibitors and methods of use thereof
WO2020231990A1 (en) * 2019-05-13 2020-11-19 Relay Therapeutics, Inc. Fgfr inhibitors and methods of use thereof
JP2022533570A (ja) * 2019-05-13 2022-07-25 リレー セラピューティクス， インコーポレイテッド Ｆｇｆｒ阻害剤およびそれらの使用
JP7527309B2 (ja) 2019-05-13 2024-08-02 リレー セラピューティクス， インコーポレイテッド Ｆｇｆｒ阻害剤およびそれらの使用
WO2021017892A1 (zh) 2019-07-26 2021-02-04 上海复宏汉霖生物技术股份有限公司 针对抗cd73抗体和变体的方法和组合物
WO2021046159A1 (en) 2019-09-04 2021-03-11 Genentech, Inc. Cd8 binding agents and uses thereof
WO2021062085A1 (en) 2019-09-27 2021-04-01 Genentech, Inc. Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies
EP4424321A2 (en) 2019-09-27 2024-09-04 F. Hoffmann-La Roche AG Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies
WO2021083949A1 (en) 2019-10-29 2021-05-06 F. Hoffmann-La Roche Ag Bifunctional compounds for the treatment of cancer
WO2021092171A1 (en) 2019-11-06 2021-05-14 Genentech, Inc. Diagnostic and therapeutic methods for treatment of hematologic cancers
WO2021097110A1 (en) 2019-11-13 2021-05-20 Genentech, Inc. Therapeutic compounds and methods of use
WO2021119505A1 (en) 2019-12-13 2021-06-17 Genentech, Inc. Anti-ly6g6d antibodies and methods of use
WO2021127404A1 (en) 2019-12-20 2021-06-24 Erasca, Inc. Tricyclic pyridones and pyrimidones
WO2021154761A1 (en) 2020-01-27 2021-08-05 Genentech, Inc. Methods for treatment of cancer with an anti-tigit antagonist antibody
WO2021177980A1 (en) 2020-03-06 2021-09-10 Genentech, Inc. Combination therapy for cancer comprising pd-1 axis binding antagonist and il6 antagonist
WO2021194481A1 (en) 2020-03-24 2021-09-30 Genentech, Inc. Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies
WO2021202959A1 (en) 2020-04-03 2021-10-07 Genentech, Inc. Therapeutic and diagnostic methods for cancer
WO2021222167A1 (en) 2020-04-28 2021-11-04 Genentech, Inc. Methods and compositions for non-small cell lung cancer immunotherapy
WO2021257503A1 (en) 2020-06-16 2021-12-23 Genentech, Inc. Methods and compositions for treating triple-negative breast cancer
WO2021257124A1 (en) 2020-06-18 2021-12-23 Genentech, Inc. Treatment with anti-tigit antibodies and pd-1 axis binding antagonists
WO2022020716A1 (en) 2020-07-24 2022-01-27 Genentech, Inc. Heterocyclic inhibitors of tead for treating cancer
WO2022031749A1 (en) 2020-08-03 2022-02-10 Genentech, Inc. Diagnostic and therapeutic methods for lymphoma
WO2022036146A1 (en) 2020-08-12 2022-02-17 Genentech, Inc. Diagnostic and therapeutic methods for cancer
WO2022066805A1 (en) 2020-09-23 2022-03-31 Erasca, Inc. Tricyclic pyridones and pyrimidones
CN116963740A (zh) * 2020-10-02 2023-10-27 麦托吉宁公司 治疗肾脏疾病和纤维化的组合物和方法
WO2022072925A1 (en) 2020-10-02 2022-04-07 Mitokinin, Inc. Compositions and methods of treating kidney disease and fibrosis
WO2022076462A1 (en) 2020-10-05 2022-04-14 Genentech, Inc. Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
US12152034B2 (en) 2020-11-18 2024-11-26 Relay Therapeutics, Inc. FGFR inhibitors and methods of making and using the same
WO2022133345A1 (en) 2020-12-18 2022-06-23 Erasca, Inc. Tricyclic pyridones and pyrimidones
WO2022171745A1 (en) 2021-02-12 2022-08-18 F. Hoffmann-La Roche Ag Bicyclic tetrahydroazepine derivatives for the treatment of cancer
WO2022251296A1 (en) 2021-05-25 2022-12-01 Erasca, Inc. Sulfur-containing heteroaromatic tricyclic kras inhibitors
WO2022266206A1 (en) 2021-06-16 2022-12-22 Erasca, Inc. Kras inhibitor conjugates
WO2023018699A1 (en) 2021-08-10 2023-02-16 Erasca, Inc. Selective kras inhibitors
US12110276B2 (en) 2021-11-24 2024-10-08 Genentech, Inc. Pyrazolo compounds and methods of use thereof
WO2023097195A1 (en) 2021-11-24 2023-06-01 Genentech, Inc. Therapeutic indazole compounds and methods of use in the treatment of cancer
WO2023097194A2 (en) 2021-11-24 2023-06-01 Genentech, Inc. Therapeutic compounds and methods of use
US12275745B2 (en) 2021-11-24 2025-04-15 Genentech, Inc. Therapeutic compounds and methods of use
WO2023191816A1 (en) 2022-04-01 2023-10-05 Genentech, Inc. Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
WO2023219613A1 (en) 2022-05-11 2023-11-16 Genentech, Inc. Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
WO2023240058A2 (en) 2022-06-07 2023-12-14 Genentech, Inc. Prognostic and therapeutic methods for cancer
WO2024015897A1 (en) 2022-07-13 2024-01-18 Genentech, Inc. Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
WO2024020432A1 (en) 2022-07-19 2024-01-25 Genentech, Inc. Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
WO2024033388A1 (en) 2022-08-11 2024-02-15 F. Hoffmann-La Roche Ag Bicyclic tetrahydrothiazepine derivatives
WO2024033458A1 (en) 2022-08-11 2024-02-15 F. Hoffmann-La Roche Ag Bicyclic tetrahydroazepine derivatives
WO2024033389A1 (en) 2022-08-11 2024-02-15 F. Hoffmann-La Roche Ag Bicyclic tetrahydrothiazepine derivatives
WO2024033457A1 (en) 2022-08-11 2024-02-15 F. Hoffmann-La Roche Ag Bicyclic tetrahydrothiazepine derivatives
WO2024085242A2 (en) 2022-10-21 2024-04-25 Kawasaki Institute Of Industrial Promotion Non-fouling or super stealth vesicle
WO2024091991A1 (en) 2022-10-25 2024-05-02 Genentech, Inc. Therapeutic and diagnostic methods for multiple myeloma
WO2024173842A1 (en) 2023-02-17 2024-08-22 Erasca, Inc. Kras inhibitors
WO2024233341A1 (en) 2023-05-05 2024-11-14 Genentech, Inc. Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
WO2024254455A1 (en) 2023-06-08 2024-12-12 Genentech, Inc. Macrophage signatures for diagnostic and therapeutic methods for lymphoma
WO2025024257A1 (en) 2023-07-21 2025-01-30 Genentech, Inc. Diagnostic and therapeutic methods for cancer
WO2025049277A1 (en) 2023-08-25 2025-03-06 Genentech, Inc. Methods and compositions for treating non-small cell lung cancer comprising an anti-tigit antagonist antibody and a pd-1 axis binding antagonist
US12173005B1 (en) 2023-12-21 2024-12-24 King Faisal University Pyrimido[1′,6′:1,5]pyrazolo[4,3-b][1,7]naphthyridine compounds as CK2 inhibitors
WO2026030464A1 (en) 2024-07-30 2026-02-05 Genentech, Inc. Dosage regimen for reducing cytokine release syndrome (crs) with anti-fcrh5/anti-cd3 bispecific antibodies in multiple myeloma therapy
WO2026030476A1 (en) 2024-07-30 2026-02-05 Genentech, Inc. Precision medicine for optimal dosage of combined therapies systems and methods of use thereof

Also Published As

Publication number Publication date
HUP9900330A2 (hu) 1999-05-28
NZ312665A (en) 1999-08-30
HK1008222A1 (en) 1999-05-07
CN1194647A (zh) 1998-09-30
EA199800116A1 (ru) 1998-10-29
DE69619114D1 (de) 2002-03-21
TR199800012T1 (xx) 1998-04-21
JPH11508570A (ja) 1999-07-27
KR100437582B1 (ko) 2004-12-17
AU6414896A (en) 1997-02-05
AU707626B2 (en) 1999-07-15
DE69619114T2 (de) 2002-10-02
SI9620103A (sl) 1998-10-31
MX9800215A (es) 1998-03-31
NO310359B1 (no) 2001-06-25
IL122855A0 (en) 1998-08-16
EP0836605B1 (en) 2002-02-06
ATE212993T1 (de) 2002-02-15
IL122855A (en) 2004-08-31
KR19990028756A (ko) 1999-04-15
NO975956D0 (no) 1997-12-18
CN1100778C (zh) 2003-02-05
BR9609617A (pt) 1999-05-25
CZ1598A3 (cs) 1998-04-15
ES2172670T3 (es) 2002-10-01
HUP9900330A3 (en) 2001-08-28
PT836605E (pt) 2002-07-31
WO1997002266A1 (en) 1997-01-23
EA001428B1 (ru) 2001-02-26
DK0836605T3 (da) 2002-05-13
PL188959B1 (pl) 2005-05-31
JP4146514B2 (ja) 2008-09-10
CA2224435A1 (en) 1997-01-23
PL324285A1 (en) 1998-05-11
EP0836605A1 (en) 1998-04-22
SK398A3 (en) 1998-07-08
CA2224435C (en) 2008-08-05
CY2365B1 (en) 2004-06-04
BR9609617B1 (pt) 2010-07-27
NO975956L (no) 1998-02-10

Similar Documents

Publication Publication Date Title
US6140332A (en) Pyrrolopyrimidines and processes for the preparation thereof
EP0938486B1 (en) Substituted pyrrolopyrimidines and processes for their preparation
DE69712745T2 (de) Pyrrolopyrimidinen und verfahren zu deren herstellung
EP0929553B1 (en) Pyrimidine derivatives and processes for the preparation thereof
EP0819129B1 (en) Pyrazole derivatives and processes for the preparation thereof
AU695244B2 (en) Pyrrolopyrimidine derivatives having pharmacological activity
AU707626C (en) Pyrrolopyrimidines and processes for the preparation thereof
HK1008222B (en) Pyrrolopyrimidines and processes for the preparation thereof
TW472057B (en) Pyrrolopyrimidines and processes for the preparation thereof

Legal Events

Date Code Title Description
AS Assignment

Owner name: NOVARTIS AG, SWITZERLAND

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:TRAXLER, PETER;BOLD, GUIDO;BRILL, WOLFGANG KARL-DIETHER;AND OTHERS;REEL/FRAME:010965/0370;SIGNING DATES FROM 19971217 TO 19980114

FEPP Fee payment procedure

Free format text: PAYOR NUMBER ASSIGNED (ORIGINAL EVENT CODE: ASPN); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

CC Certificate of correction
FPAY Fee payment

Year of fee payment: 4

FPAY Fee payment

Year of fee payment: 8

REMI Maintenance fee reminder mailed
LAPS Lapse for failure to pay maintenance fees
STCH Information on status: patent discontinuation

Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362

FP Lapsed due to failure to pay maintenance fee

Effective date: 20121031